Multi-Receptor Agonists

Question 1

Bariatric surgery

Answer 1

• Roux-en-Y gastric bypass is best in class
• causes substantial and usually maintained weight loss
• facilitated by decreased appetite
• and can resolve diabetes as weight loss increases insulin sensitivity

Question 2

Caloric restriction

Answer 2

• nutrient excess beyond fat storage = fat accumulation in ectopic sites = tissue dysfunction
• small calorie deficit may allow loss of ectopic fat and reverse metabolic disturbance
• sustained deficit allows weight loss and increased insulin sensitivity
• restriction does not decrease desire to eat in same way that surgery does

Question 3

Injectable peptides

Answer 3

• semaglutide = GLP1R agonist for T2D and obesity
• trialling GLP1 and amylin dual therapy
• developing triple agonists e.g. GLP1, glucagon etc

Question 4

GLP1R and glucagon

Answer 4

• GLP1R increases insulin and decreases food intake
• glucagon decreases food intake despite increasing hepatic glucose production
• cotadutide = phase II for T2D and obesity (GLP1 + glucagon dual agonist) = withdrawn due to market movement to weekly dosing
• retatrutide - GLP1/GIP/glucagon triple agonist

Question 5

Tirzepatide

Answer 5

• best in class drug for T2D/obesity
• dual GIP and GLP1R agonist

Why is it better?
better tolerated than GLP1R agonist due to decreased nausea?
- so can use higher concentration
- no evidence of clinical dose being higher though!

GIPR agonism beneficial?
- GIPR in islets = increased insulin and glucagon and somatostatin
- agonism in adipose tissue = increased blood flow = increased lipid storage = increased lipolysis in low insulin conditions
- GIP decreases food intake in mouse models via GIPR in the brainstem and hypothalamus
- but GIP concentrations are too low in humans to do this as inactivated by DPP4!

Question 6

GIP and body weight

Answer 6

• GIPR KO mice = protected from diet-induced obesity
• human GIPR mutants = decreased weight
• could GIPR antagonists be useful? e.g. maritide
• GIPR agonism and antagonism both improve weight loss alone and with GLP1R agonism
• likely target different cell populations
• should take caution if antagonising as human mutants have reduced bone density and BMI