Incretin polyagonists as an alternative to bariatric surgery to manage obesity

Table 1 A Summary of the pharmacology of incretin analogues[9,16,17]

Drug	Mechanism of action	Contraindications	Side effects	Peculiar features
Tirzepatide	Dual GLP-1/GIP receptor agonist	Personal/family history of medullary thyroid carcinoma; MEN2; hypersensitivity to drugs	GI upset (nausea, vomiting, diarrhea), increased heart rate, and possible gallbladder/biliary disease	Greatest body weight loss among incretin dual agonists; weekly injection; potent glucose-lowering effects
Mazdutide (LY3305677)	Dual GLP-1/glucagon receptor agonist	Same as above (GLP-1 class), caution in pancreatitis	GI upset, increased heart rate, possible transient hyperglycemia	Also reduces liver fat; superior effect on dyslipidemia/liver enzymes; once-weekly injection
Cotadutide	Dual GLP-1/glucagon receptor agonist	As above, severe GI disease	GI upset (nausea/diarrhea mostly), mild increase in heart rate	Strong hepatic fat/lipid-lowering effects; less potent on body weight than the GIP combination
Survodutide	Dual GLP-1/glucagon receptor agonist	As above	GI symptoms (similar to GLP-1), ↑heart rate	Potent weight and liver fat reduction; phase 3 for obesity and MASH
SAR425899	Dual GLP-1/glucagon receptor agonist	As above	GI upset, possible increased heart rate	Early clinical studies: Moderate efficacy
Retatrutide	Triple GLP-1/GIP/glucagon receptor agonist	As above, caution in severe heart disease	GI upset is very common; increased heart rate, and some reports of mild hypoglycemia	Highest %body weight loss (up to 24%); reduces hepatic fat, robust metabolic effects
Efocipegtrutide	Triple GLP-1/GIP/glucagon receptor agonist	As above	GI side effects, increased heart rate	In the early clinical stage of development, phase 2 trials are ongoing
Semaglutide + cagrilintide	GLP-1 and amylin analogue co-agonist	As above: Severe GI disease; gastroparesis	Nausea, vomiting (higher than semaglutide alone), constipation	Superior weight loss to monotherapies; once-weekly injection; appetite suppression
PYY/GLP-1 and other gut hormone combos	Multi-gut hormone co-agonism varies per molecule	Unknown, not established yet	GI upset (anticipated), long-term safety data pending	Aims to mimic post-bariatric physiology; most are in early development

GLP-1: Glucagon-like polypeptide-1; GIP: Glucose-dependent insulinotropic polypeptide; PYY: Peptide YY; MEN2: Multiple endocrine neoplasia type 2; GI: Gastro-intestinal; MASH: Metabolic dysfunction-associated steatohepatitis.