Table 3 Influence of GLP-1, GIP, their combination, and tirzepatide (dual GIP/GLP-1 receptor co-agonist) on determinants of glycaemic control and body weight in healthy and type 2-diabetic human subjects
Parameter/Population studied | Previous findings regarding short-term exposure to | Current findings with long-term exposure to | ||
|---|---|---|---|---|
GLP-1 | GIP | Combination of GLP-1 and GIP | Tirzepatide (dual GIP/GLP-1 receptor co-agonist) | |
Insulin secretion | ||||
 Healthy subjects | Glucose-dependent stimulation [55] | Not studied | ||
 Type 2 diabetes patients | Much-reduced glucose-dependent stimulation (almost no effect) [7, 59] | Not different from effects of GLP-1 alone (negligible effects of GIP) [8] | Stimulated more than with selective GLP-1 RA semaglutide [50] (suggesting some effect of GIPR agonism) | |
Glucagon secretion | ||||
 Healthy subjects | Little effect at moderate hyperglycaemia [7], no effect at hypoglycaemia [60] | Stimulation (dependent on plasma glucose concentrations) [61] | Not studied | Not studied |
 Type 2 diabetes patients | No significant effect at moderate hyperglycaemia [7, 8], stimulation at low plasma glucose [62] | No effect (i.e., the GLP-1-induced suppression is counteracted by concomitant exposure to GIP [8]) | Suppression (greater than suppression with selective GLP-1 RA semaglutide) [50] (suggesting some effect of GIPR agonism) | |
Insulin sensitivity | ||||
 Healthy subjects | No acute effects [63] | Not studied | Not studied | Not studied |
 Type 2 diabetes patients | No acute effects [64] | Not studied | Not studied | Increased with long-term administration (accompanied by substantial weight loss), more than with the selective GLP-1 RA semaglutide [50] |
Meal tolerance | ||||
 Healthy subjects | Not studied | Not studied | Not studied | Not studied |
 Type 2 diabetes patients | Improved [65] (mainly through deceleration of gastric emptying) | Slightly worsened [66] (stimulation of glucagon) | Not studied | Improved (more than with selective GLP-1 RA semaglutide) [50] |
 Glycated haemoglobin (HbA1c) Type 2 diabetes patients | Reduced [67] | Not studied | Not studied | Greater reduction in fasting plasma glucose and HbA1c as compared to selective GLP-1 RAs (e.g., dulaglutide [14] or semaglutide [16]) |
 Appetite Healthy or non-diabetic obese subjects | Reduced (robust findings) [68] | Not changed [69] | Not changed [69] | Appetite reduced with tirzepatide and semaglutide (selective GLP-1 RA) to a similar degree [49] |
 Caloric intake (ad libitum meal) Healthy or non-diabetic obese subjects | Not changed [69] | Less reduction compared to GLP-1 alone [69] | Similar reduction compared to selective GLP-1 RA semaglutide [49] | |
 Energy expenditure Healthy or non-diabetic obese subjects | Not changed [69] | Not changed [69] | Not changed [69] | Not studied |
 Body weight Type 2 diabetes patients | Reduced after 6 weeks of s.c. infusion [67] | Not studied | Not studied | Substantial reduction (see Fig. 3; more than with selective GLP-1 RA semaglutide) [50] |