Weight Loss Peptides

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Incretin-Based Therapies

Semaglutide vs Tirzepatide vs Retatrutide

High-level comparison of three modern incretin-based peptides under clinical investigation and/or use for type 2 diabetes and obesity.

Semaglutide (GLP-1) Tirzepatide (GIP/GLP-1) Retatrutide (GIP/GLP-1/Glucagon)
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Information only — not medical advice.
These are potent prescription (or investigational) medications with significant risks and contraindications. Any use or change in therapy must be supervised by a licensed clinician.
Robust human data Emerging human data Early-stage / investigational
Semaglutide GLP-1 receptor agonist
Weight Loss Appetite Reduction Type 2 Diabetes Cardiometabolic Support
Robust human data

Core Mechanism

  • Selective GLP-1 receptor agonist.
  • Enhances glucose-dependent insulin secretion and suppresses glucagon.
  • Slows gastric emptying and reduces appetite via central pathways.

Approved Uses

  • Type 2 diabetes (Ozempic, Rybelsus).
  • Chronic weight management (Wegovy).

Clinical Highlights

  • ~10–15% mean weight loss at higher doses.
  • Improves A1c and cardiometabolic markers.

Key Safety Notes

  • Common GI effects: nausea, vomiting, constipation, appetite loss.
  • Warnings: pancreatitis, gallbladder disease, thyroid tumor risk in rodents.
Tirzepatide Dual GIP/GLP-1 agonist
Weight Loss Type 2 Diabetes Insulin Sensitivity Metabolic Repair
Robust human data

Core Mechanism

  • Acts on both GIP and GLP-1 receptors.
  • Enhances insulin secretion, reduces glucagon, strongly suppresses appetite.
  • GIP component may improve tolerability or augment weight-loss effects.

Approved / Investigated Uses

  • Type 2 diabetes (Mounjaro).
  • Chronic weight management (Zepbound).

Clinical Highlights

  • Often produces >20% weight loss in higher-dose trials.
  • Major improvements in A1c and insulin resistance.

Key Safety Notes

  • GI side effects similar to GLP-1 class.
  • Warnings for pancreatitis, gallbladder disease, thyroid tumors (class warning).
Retatrutide Triple GIP/GLP-1/Glucagon agonist
Obesity Metabolic Disease High-Impact Weight Loss Energy Expenditure
Emerging human data

Core Mechanism

  • Triple agonist: GIP + GLP-1 + glucagon.
  • Incretin effects for insulin secretion and appetite reduction.
  • Glucagon agonism increases energy expenditure and fat oxidation.

Development Status

  • As of 2025: investigational drug in clinical trials.
  • Being studied for obesity, diabetes, and cardiometabolic conditions.

Clinical Highlights (Early Data)

  • Phase 2 results show some of the strongest weight-loss percentages ever recorded in trials.
  • Marked glucose & lipid improvements but long-term durability unknown.

Key Safety Notes

  • GI effects similar to GLP-1/GIP drugs.
  • Full safety profile still emerging due to glucagon component.

Incretin Therapies at a Glance

Drug Receptor Targets Primary Indications Weight-Loss Signal Evidence Level Key Safety / Notes
Semaglutide GLP-1 receptor agonist Type 2 diabetes; chronic weight management in obesity/overweight with comorbidities. ~10–15% mean loss at higher doses in many trials; substantial A1c and cardiometabolic benefits. Robust human data; widely approved. GI symptoms common; risk of pancreatitis, gallbladder disease; boxed warning for thyroid C-cell tumors (rodent data).
Tirzepatide Dual GIP/GLP-1 agonist Type 2 diabetes; chronic weight management in obesity/overweight. Often >20% loss in some high-dose cohorts; very strong improvements in glycemic control. Robust human data; approved for T2D and obesity. Similar GI profile to GLP-1 agonists, sometimes more intense; same class warnings for pancreatitis, gallbladder disease, thyroid C-cell tumors.
Retatrutide Triple GIP/GLP-1/Glucagon agonist Investigational for obesity, T2D, and metabolic disease. Very large weight-loss percentages in early trials, possibly exceeding current agents. Emerging human data; not yet widely approved. GI effects and metabolic shifts require close monitoring; long-term cardiovascular and safety outcomes still under study.