Are there any peptides other than Glucagon-like peptide-1 (GLP-1) that have health benefits supported by data?

Peptides Beyond GLP-1 Receptor Agonists with Evidence-Based Health Benefits

Yes, there are several other peptide-based therapies with robust data supporting health benefits, most notably dual and triple incretin receptor agonists (GIP/GLP-1 and GIP/GLP-1/glucagon combinations) that demonstrate superior efficacy to single GLP-1 agonists for weight loss and metabolic outcomes.

Dual GIP/GLP-1 Receptor Agonists

Tirzepatide represents the most clinically advanced dual agonist with compelling evidence for superior metabolic benefits compared to single GLP-1 agonists. 1

• Tirzepatide achieved mean weight loss of 15% at 72 weeks in non-diabetic obese patients, with up to 20.9% weight reduction at the 15 mg dose - substantially exceeding single GLP-1 agonist efficacy 1
• This dual GIP/GLP-1 receptor agonist demonstrated weight loss comparable to bariatric surgery in patients with type 2 diabetes 1
• Tirzepatide significantly reduced both liver fat and visceral adipose tissue in patients with type 2 diabetes, with promising phase II results showing steatohepatitis resolution in MASH patients 1
• The mechanism combines GLP-1's effects on insulin secretion and appetite suppression with GIP's additional metabolic actions 1

Dual GLP-1/Glucagon Receptor Agonists

Several dual GLP-1/glucagon agonists show promise for metabolic disease, though they remain in earlier development stages compared to tirzepatide. 1

• Cotadutide and efinopegdutide both improved liver steatosis, liver enzymes, and fibrosis indices in patients with MASLD 1
• Survodutide demonstrated promising weight-loss effects with encouraging preliminary histology data from phase IIb trials 1
• These agents add glucagon's effects on lipolysis, lipid oxidation, and energy expenditure to GLP-1's actions 1

Triple GIP/GLP-1/Glucagon Receptor Agonists

Retatrutide, a triple agonist, represents the next generation of incretin-based therapy with potential for bariatric surgery-level weight loss. 1

• Triple agonists combine the anorexigenic effects of GLP-1 with GIP and glucagon's peripheral metabolic effects including increased lipolysis and energy expenditure 1
• These agents can induce weight loss magnitude similar to bariatric surgery 1
• Clinical histology data are still pending for these newer agents 1

SGLT-2 Inhibitors (Not Peptides, But Important Context)

While SGLT-2 inhibitors are not peptides, they warrant mention as the evidence shows clear differentiation in cardiovascular benefits: SGLT-2 inhibitors primarily reduce heart failure complications, while GLP-1 agonists primarily prevent atherosclerotic events 1

• SGLT-2 inhibitors demonstrated reduction in heart failure hospitalization and cardiovascular mortality in patients with and without diabetes 1
• For patients at risk of heart failure, SGLT-2 inhibitors should be preferred over GLP-1 agonists 1
• GLP-1 agonists show no clear benefit on heart failure hospitalization and have uncertain safety in heart failure with reduced ejection fraction 1

Clinical Implications

The choice between single, dual, or triple agonists should prioritize the magnitude of weight loss needed and specific metabolic complications present:

• For maximum weight loss approaching bariatric surgery levels: Consider tirzepatide (dual) or retatrutide (triple) when available 1
• For patients with MASLD/MASH: Dual GLP-1/glucagon agonists show specific benefits on liver histology 1
• For cardiovascular disease prevention: Single GLP-1 agonists (semaglutide, liraglutide) have the most robust cardiovascular outcome trial data 1
• For heart failure risk: SGLT-2 inhibitors are superior to any incretin-based therapy 1

Important Caveats

• None of these dual or triple agonists have completed large phase III trials with histological endpoints for MASH, so they cannot yet be recommended as MASH-targeted therapies despite promising signals 1
• All incretin-based therapies carry risks of delayed gastric emptying, with implications for perioperative aspiration risk 1
• Common adverse effects (nausea, vomiting, diarrhea) are dose-dependent and may be more pronounced with dual/triple agonists 1