Table 7.

Glucagon Like Peptide – 1 Receptor Agonism Combinations. Many anti-obesity drugs in development combine a GLP-1 RA with other investigational drug/s, resulting in dual or triple mechanisms of action [170].

Glucagon Like Peptide – 1 Receptor Agonist (GLP-1 RA) PLUS
Therapeutic agent	Mechanism	Notes
Agonists of both GLP-1 receptor and glucose-dependent insulinotropic polypeptide (GIP) receptors, with the latter previously known as gastric inhibitory peptide	Functions as an unimolecular GLP-1 and GIP receptor agonist. While some do not recognize it as a medical term, "twincretin” is often used to describe agents that increase the activity of two incretins.	Tirzepatide is approved for treatment of type 2 diabetes mellitus, and is in development for treatment of obesity. Within its SURPASS development program (focused on type 2 diabetes), studies include the SURPASS CVOT, which is a large phase 3 clinical trial evaluating the cardiovascular outcomes of tirzepatide versus dulaglutide among patients with type 2 diabetes mellitus [[162], [163], [164]] and the SURMOUNT program for chronic weight management in patients with overweight or obesity (See Chart 3).
GLP-1 RA combined with GIP antagonists	GIP receptor knockout mice develop resistance toward diet-induced obesity, and those with inactivated mutations of GIP receptor have reduced body weight. Antagonizing GIP may also be advantageous in glucose control via reducing GIP-mediated glucagon secretion.	It may seem paradoxical that GLP-1 RA plus either GIP agonists (described above) or GIP antagonists may promote weight reduction and similar metabolic benefits. A possible explanation is that GIP agonists chronically activate the GIP receptor, causing desensitization and receptor internalization, thus downregulating the GIP system in a way that it mimics antagonism [157,165].
GLP-1 RA combined with glucagon (GCG) receptor agonist (GCG-RA)	While glucagon may increase glucose levels via gluconeogenesis and inhibition of insulin, glucagon may also decrease hunger, increase satiety, have catabolic and thermogenic effects, increase energy expenditure, increase lipolysis and fatty acid oxidation, and reduce cholesterol and triglyceride levels.	Oxyntomodulin is an illustrative example of a unimolecular dual agonist of GLP-1 and glucagon. While glucagon alone would be expected to raise glucose levels, the net effect of GLP-1 RA and GCG-RA is weight reduction, decrease hunger, increased satiety, reduction in glucose, cholesterol, and triglyceride levels, and possible increase in energy expenditure [165,166]. Examples of GLP-1/GCG dual agonists include cotadutide, efinopegdutide, BI 456906, pemvidutide, and oxyntomodulin analogues [164].
GLP-1 RA combined with agonists of GIP & GCG	Complementary actions from activation of three components (GLP-1, GIP, and GCG)	Tri-agonist [167]
GLP-1 RA combined with Peptide YY (PYY)	Increase satiety, decrease hunger	Some PYY agents evaluated for monotherapy of obesity resulted in unacceptable nausea and vomiting and limited weight reduction [165,168].
GLP-1 RA combined with amylin	Increase satiety, decrease hunger	Amylin may promote weight reduction and increase sensitivity to leptin in patients with obesity. Cagrilintide is a long-acting amylin analogue [169,164].