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.

Table 2 Recent studies and trials on anti-obesity medications and bariatric surgery for obesity treatment

Ref.	Study type	Population/setting	Comparison groups	Main outcomes	Complications/notes
Dicker et al[36], 2024	Large retrospective matched cohort	6070 adults with obesity and diabetes; Israel, 2008-2022; median 6.8 years follow-up	MBS vs GLP-1 RAs	MBS: 62% reduction in mortality vs GLP-1 RAs for diabetes ≤ 10 years. No difference if diabetes > 10 years. Weight loss: MBS (-31.4% BMI) vs GLP-1 RAs (-12.8%). No difference in MACEs	MBS survival benefit mediated by greater weight loss. Similar glycemic control long term. Complications were not directly compared
American Society for Metabolic and Bariatric Surgery[32]	Real-world retrospective comparative study	51085 adults BMI ≥ 35, New York city 2018-2024	Bariatric surgery (sleeve gastrectomy or gastric bypass) vs GLP-1 RAs (semaglutide, tirzepatide)	2 years: Bariatric surgery = 58-pound average loss (24% body weight); GLP-1 = 12-pound average (4.7%), 7% for those on drugs all year. Surgery: About 5 times more weight loss	Over 50% discontinued GLP-1 in 1 year, 72% by 2 years. Surgery is more durable. Complication rates for surgery are not detailed, but surgery is found to be effective and safe
Yan et al[37], 2019	Meta-analysis (4 RCTs, 6 cohorts)	Adults with severe obesity and T2DM (> 5 years follow-up)	Bariatric surgery vs conservative (non-surgical, includes meds and lifestyle)	Bariatric surgery: Lower macrovascular complications (RR = 0.43), lower MI (RR = 0.40), and greater weight and glycemic improvement	Surgery is superior for CV outcomes and weight. Complications depend on the surgical type, but risks are higher than with medication
Newman[38], 2025	Review/expert summary	General adult obesity population	Bariatric surgery vs anti-obesity medications	Bariatric surgery provides greater and longer-lasting weight loss compared to anti-obesity meds	Surgery: More durable weight loss. Meds are easier to administer and reversible, but have fewer profound effects
Courcoulas et al[39], 2024	Pooled RCTs (7-12 years follow-up)	Diabetes + obesity/overweight	Surgery vs medical/lifestyle	Surgery: Greater long-term weight loss, improved glycemic control, and increased diabetes remission	Surgery: Higher long-term risk of nutritional deficiencies, GI events, and fractures. Meds have a lower risk profile but less efficacy
Lincoff et al[40], 2023	Randomized, double-blind, placebo-controlled trial	17604 adults (BMI ≥ 27) with preexisting CV disease, no diabetes; 41 countries, mean 39.8 months follow-up	Semaglutide 24 mg weekly vs placebo	Semaglutide: 6.5% CV events vs placebo: 8.0% (HR = 0.80, 95%CI: 0.72-0.90, P < 0.001). Reduced death from CV causes, nonfatal MI, or nonfatal stroke	More adverse events led to discontinuation in the semaglutide group (16.6% vs 8.2%). No surgery arm. Strong CV benefit among anti-obesity drugs in high-risk patients without diabetes
Hernandez et al[41], 2018	Randomized, double-blind, placebo-controlled trial	9463 adults with T2DM and established cardiovascular disease, global, median 1.6 years follow-up	Albiglutide 30-50 mg weekly vs placebo	Primary composite (CV death, MI, stroke): 7% albiglutide vs 9% placebo (HR = 0.78, 95%CI: 0.68-0.90; superiority P = 0.0006)	Incidence of acute pancreatitis, pancreatic cancer, and medullary thyroid carcinoma is low and not different between groups. Confirms the CV benefit of GLP-1 RA in T2DM with CVD

RCT: Randomized controlled trial; BMI: Body mass index; T2DM: Type 2 diabetes mellitus; CV: Cardiovascular; MBS: Metabolic or bariatric surgery; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; MACE: Major adverse cardiovascular event; RR: Relative risk; MI: Myocardial infarction; HR: Hazard ratio; CI: Confidence interval; GI: Gastro-intestinal; CVD: Cardiovascular disease.