Semaglutide (GLP-1 Receptor Agonist)
An FDA-approved GLP-1 receptor agonist for type 2 diabetes and obesity. The most widely prescribed weight loss medication in history, available as Ozempic (diabetes), Wegovy (weight loss), and Rybelsus (oral).
Semaglutide mimics a natural hormone (GLP-1) that tells your brain you're full, tells your pancreas to release insulin when blood sugar is high, and slows down digestion so food stays in your stomach longer. The net effect: you eat less, feel satisfied sooner, blood sugar improves, and you lose weight. The weekly injection lasts 7 days because it's designed to stick to a protein in your blood.
The most effective approved weight loss medication. 14.9% average weight loss in STEP 1. Strong appetite suppression. FDA-approved for obesity (BMI 30+ or 27+ with comorbidity).
Improves virtually every metabolic marker: HbA1c, fasting glucose, insulin sensitivity, triglycerides, LDL, hs-CRP. FDA-approved for T2DM.
SELECT trial showed 20% reduction in MACE. Improves lipids, reduces inflammation, reduces blood pressure.
Being studied for NASH. Reduces liver fat and ALT/AST. Phase 3 NASH trials underway.
Reduces inflammation, improves metabolic health, reduces CV risk. These are all aging-relevant endpoints. Not a primary anti-aging peptide but significant indirect benefits.
Being studied for Alzheimer's disease (EVOKE trial). GLP-1 receptors present in brain. Neuroprotective effects in preclinical models. Too early for conclusions.
May improve sleep apnea through weight loss. Some reports of improved sleep quality.
Weight loss may improve testosterone and libido in obese men. Not a direct effect.
Actively counterproductive for muscle growth. 25-40% of weight lost is lean mass. Must combine with resistance training and high protein to mitigate.
Not relevant.
Semaglutide activates GLP-1 receptors in the pancreas, brain, and gut. Pancreatic effects: stimulates glucose-dependent insulin secretion, suppresses glucagon release, and slows beta-cell decline. CNS effects: acts on hypothalamic appetite centers to reduce hunger and increase satiety. GI effects: delays gastric emptying, increasing fullness. Cardiovascular effects: reduces inflammation, improves endothelial function, and reduces atherosclerosis. The C18 fatty acid modification enables albumin binding, protecting against DPP-4 degradation and extending half-life to ~7 days.
FDA-approved protocol. Gradual dose escalation minimizes GI side effects. Many patients settle at 1.0-1.7mg if 2.4mg causes excessive nausea.
Lower doses than Wegovy. Primary endpoint is glycemic control, weight loss is secondary benefit.
Must take on empty stomach with small amount of water. No food, drink, or other meds for 30 minutes. Bioavailability is only ~1% but sufficient for glycemic control. Less weight loss than injectable.
Most common side effect (30-44% in trials). Usually decreases with dose escalation and time.
Rapid weight loss increases gallstone risk. Cholecystitis reported in trials.
Acute pancreatitis reported. Discontinue if suspected. Risk appears low but FDA black box adjacent.
Black box warning based on rodent studies showing medullary thyroid carcinoma. Not confirmed in humans but contraindicated in MEN2/MTC history.
25-40% of weight lost may be lean mass. Resistance training and adequate protein (1g/lb) strongly recommended.
Mechanism of action includes slowed gastric emptying. In some patients this becomes pathological.
FDA black box warning. GLP-1 RAs caused thyroid C-cell tumors in rodents. Contraindicated in MTC or MEN2 syndrome.
FDA black box warning.
Increased risk of acute pancreatitis. Use with caution, discontinue if pancreatitis suspected.
Animal studies show fetal harm. Discontinue at least 2 months before planned pregnancy due to long half-life.
Not indicated and may increase risk of ketoacidosis.
Increased risk of hypoglycemia when combined. Dose adjustment of insulin/SU may be needed.
Semaglutide further delays gastric emptying.
Appetite suppression effects may interact with disordered eating patterns.
Rapid weight loss increases gallstone risk.
GI side effects (dehydration from vomiting) can worsen renal function. Monitor in CKD patients.
Reduces HbA1c by 1.5-1.8% in clinical trials. Primary endpoint for diabetes indication.
Glucose-dependent insulin secretion and glucagon suppression.
Improves insulin sensitivity. Fasting insulin decreases as insulin resistance improves.
Significant triglyceride reduction in clinical trials.
Modest LDL reduction, primarily from weight loss.
Modest improvement.
Anti-inflammatory effects demonstrated in SELECT trial and others.
Reduction associated with cardiovascular benefit.
Liver enzyme improvement, especially in NASH patients. Being studied for NASH indication.
14.9% average weight loss at 2.4mg in STEP 1 (68 weeks). Most effective approved weight loss medication.
Do not combine GLP-1 agonists. Tirzepatide is an alternative, not a stack.
No known interactions. Different mechanisms and targets.
GH secretagogues can worsen insulin resistance. Monitor blood glucose if combining. Some practitioners use both but with careful metabolic monitoring.
MK-677 increases blood glucose and insulin resistance. Potentially counterproductive with semaglutide's metabolic benefits.
Same concern as other GH-releasing peptides regarding insulin sensitivity.
Wilding JPH, Batterham RL, Calanna S, et al. - N Engl J Med (2021) - RCT (Phase 3) - n=1961
2.4mg semaglutide weekly produced 14.9% mean weight loss vs 2.4% placebo over 68 weeks. 86.4% achieved >5% weight loss. 69.1% achieved >10%.
Limitations: Industry-funded (Novo Nordisk). Weight regain common upon discontinuation.
Rubino D, Abrahamsson N, Davies M, et al. - JAMA (2021) - RCT (Phase 3) - n=902
Continued semaglutide after 20-week run-in: additional 7.9% weight loss vs 6.9% weight regain in those switched to placebo. Demonstrates weight regain on discontinuation.
Limitations: Industry-funded.
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. - N Engl J Med (2023) - RCT (Phase 3) - n=17604
20% reduction in major adverse cardiovascular events (MACE) with semaglutide 2.4mg vs placebo in overweight/obese patients with established CV disease but without diabetes. Landmark trial establishing CV benefit independent of diabetes.
Limitations: Only studied patients with established CV disease. Industry-funded.
Gadelmawla AF, et al. - Am J Cardiol (2026) - Systematic review/meta-analysis
CagriSema (semaglutide + cagrilintide) associated with superior weight loss vs semaglutide alone. Next generation combination therapy.
Limitations: Meta-analysis of limited early trials.
Semaglutide is the most mainstream peptide due to Ozempic/Wegovy brand awareness. r/Semaglutide (500K+ members) is larger than r/Peptides. Community discussion focuses on: dose titration strategies to minimize nausea, compounded vs branded cost ($300-1500/mo branded, $100-300 compounded), muscle preservation strategies (protein intake, resistance training), and managing 'Ozempic face' (facial fat loss). Common advice: take dose on same day each week, eat protein-first meals, lift weights 3-4x/week, supplement with creatine. The 'food noise' elimination is the most commonly praised effect. Weight regain on discontinuation is the most commonly discussed concern.
FDA-approved prescription medication. Ozempic (T2DM), Wegovy (obesity), Rybelsus (oral, T2DM). Requires prescription. Compounded versions subject to FDA enforcement. Schedule: not a controlled substance.
Semaglutide requires a prescription in the US. Compounding pharmacies were producing it at lower cost, but FDA has been enforcing against this as the shortage has eased. It is NOT available as a research chemical. Any non-prescription semaglutide is either compounded (gray area) or counterfeit. Novo Nordisk holds patents through 2032+. PepStack links to licensed telehealth providers for this peptide, not research chemical vendors.
Tier 1 -- FDA-approved with multiple large-scale RCTs. STEP trials (n=1961-3731), SUSTAIN trials (n=1231-3297), PIONEER trials (oral), SELECT trial (n=17,604 for cardiovascular outcomes). The most extensively studied peptide therapeutic in history for metabolic indications.
Disclaimer: This information is for educational and research purposes only. PepStack does not provide medical advice, diagnosis, or treatment recommendations. Consult a qualified healthcare provider before using any peptide or supplement. Research suggests these compounds may have various effects, but individual results vary and many claims require further clinical validation.