Once released into the circulation, GLP-1 binds to a specific GLP-1 receptor, which is expressed in the pancreas, gastrointestinal tract, kidney, heart and brain [ 7 ]. In additional to the well-known insulinotropic property in response to nutrients in the gut, GLP-1 has a glucagonostatic effect, inhibiting glucagon secretion in the hyperglycaemic and normoglycaemic state but not during hypoglycaemia.
Extrapancreatic properties of GLP-1 include slowing of gastric emptying, promoting satiety and reducing food intake [ 8 ]. GIP is a 4 amino acid peptide, produced by the K cells of the intestine, mainly located in the duodenum and proximal jejunum. GIP is released in response to oral nutrients, especially carbohydrates and lipids. GIP receptors are present in various tissues such as the pancreas, adipose tissue, gastric mucosa, heart, adrenal cortex, bone and brain [ 7 ].
Endogenous GIP also stimulates glucose-dependent insulin secretion and is responsible for a greater proportion of the incretin effect than GLP-1 [ 9 , 10 ]. Unlike GLP-1, GIP has dual functions: a glucagonotropic property in the normoglycaemic and hypoglycaemic state, and glucagonostatic in the hyperglycaemic state [ 11 ]. The effect of GIP on adipose tissue and body weight regulation has yet to be established.
Some studies reported that GIP receptor knockout mice, unlike control mice, were resistant to diet-induced obesity [ 12 ], suggesting the adipogenic effect, whereas other studies demonstrated that chronic elevation of GIP concentrations in a transgenic mouse reduced diet-induced obesity and promoted insulin sensitivity, glucose tolerance and beta cell function [ 13 ]. Since GIP is found to have glucagonotropic properties, the other hypothetical mechanism for GIP-induced weight loss is through the anorexic and anti-lipogenic effect of glucagon [ 11 ].
The incretin effect is significantly reduced in patients with T2DM, compared to people without diabetes [ 7 ]. The proposed mechanisms behind the loss of incretin effect include 1 a reduction in incretin hormone response to nutrients hyposecretion and 2 a reduction in insulinotropic effect on pancreatic beta cells. Early studies showed that there was hyposecretion of GLP-1 in people with T2DM [ 14 , 15 ], but emerging evidence does not support this observation [ 16 ].
In fact, reduction in insulinotropic effect of GLP-1 was observed in patients with T2DM [ 17 ] and supraphysiological doses of GLP-1 receptor agonists were found to partly restore the incretin effect. However, GIP resistance, a complete loss of insulinotropic effect of GIP at physiological concentrations as well as supraphysiological concentrations was observed in people with T2DM [ 17 , 21 ].
In addition, some studies found that the glucagonotropic effect of GIP persists even in the hyperglycaemic state [ 22 ]. However, emerging evidence suggests that GIP resistance can be modified and restored by improving glycaemic control. GIP receptors on pancreatic beta cells are downregulated owing to chronic hyperglycaemia, resulting in subsequent loss of insulinotropic effect.
In a study by Hojberg et al. A potential additional benefit of GIP is safeguarding against hypoglycaemia. GIP infusion was associated with lower glucose infusion requirement to maintain a desired level of blood glucose during an insulin-induced hypoglycaemic clamp [ 24 ].
Co-administration of GIP and a GLP-1 receptor agonist RA in healthy individuals has a additive effect, generating a significantly increased insulin response compared with separate administration of each hormone [ 9 , 25 ]. Furthermore, the combined infusion produced a significant glucagonostatic effect while separate administration of GIP or GLP-1 did not suppress glucagon secretion more than glucose alone [ 25 ].
In animal studies, GIP and GLP-1 receptor co-agonist therapy at 1—3 weeks produced a dose-dependent reduction in blood glucose, body weight, food intake and fat mass compared to placebo, equimolar dose of exendin-4 or liraglutide. The co-agonist can be modified by attaching a polyethylene glycol PEG or a carbon acyl chain to extend half-life allowing weekly dosing. After 6 weeks, a dose-dependent decrease in HbA1c compared to placebo was observed.
The co-agonist was well tolerated with mild to moderate GI side effects and no hypoglycaemic events [ 29 ]. It is attached to a carbon fatty diacid moiety, which binds to albumin, prolonging its half-life to 5 days and thus enabling once weekly dosing. The clinical efficacy, safety and tolerability of tirzepatide has been reported in phase 1 and phase 2 clinical trials Table 2.
Summary of phase 1 and phase 2 trials of tirzepatide for the treatment of T2DM. Phase 1 Japanese trial [ 31 ]. Phase 2 trial [ 32 ]. Phase 2 [Dose escalation] trial [ 33 ]. A phase 1 proof-of-concept clinical trial was conducted in 53 people with T2DM, comprising five groups: two fixed dose groups tirzepatide 0.
The study had 4 weeks treatment followed by 4 weeks safety follow-up. Baseline characteristics of study participants were mean age After 4 weeks treatment, a statistically significant dose-dependent reduction in HbA1c was observed in both titration groups compared to placebo.
Fasting glucose and fasting serum insulin were significantly decreased in both titration groups compared to placebo. All tirzepatide treatment doses except 0. Similarly, 7-point self-monitoring of blood glucose demonstrated reduction in postprandial glucose levels in a dose-dependent manner. Similar to the HbA1c reduction, a dose-dependent reduction in body weight in tirzepatide groups compared to the placebo group was observed.
The 0. A similar phase 1 placebo-controlled, randomised study of tirzepatide was conducted in 48 Japanese people with T2DM. The treatment arm of the Japanese study consisted of one fixed 5 mg dose group and two dose-titration groups 2.
The study had a treatment exposure of 8 weeks with a 4-weeks safety follow-up. Baseline characteristics were mean age Significant reduction in body weight was also noted in all three tirzepatide groups weight loss of 1.
The phase 2 trial of tirzepatide was a week, placebo-controlled, double-blind, randomised trial in people with T2DM treated with lifestyle intervention alone with or without metformin monotherapy. The trial consisted of two fixed dose 1 mg and 5 mg tirzepatide groups and two dose-titration groups 5 mg for 2 weeks and 10 mg for the remaining trial period; and 5 mg for 2 weeks, 10 mg for 4 weeks and 15 mg for the remaining trial period.
There was also a dulaglutide 1. The 5 mg, 10 mg and 15 mg tirzepatide doses demonstrated a greater reduction in HbA1c at 26 weeks, compared with dulaglutide 1. Tirzepatide also resulted in significant weight loss during the trial period.
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