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The Peptide Effect
Comparison

Semaglutide vs Liraglutide

Semaglutide and liraglutide are both GLP-1 receptor agonists made by Novo Nordisk, but they represent a significant generational improvement. Liraglutide (Victoza/Saxenda), approved in 2010, requires daily injections and produces ~8% weight loss. Semaglutide (Ozempic/Wegovy), a structurally optimized successor approved in 2017, achieves ~15% weight loss with once-weekly dosing thanks to superior albumin binding and enzymatic resistance. The STEP 8 head-to-head trial directly confirmed semaglutide's superiority, showing nearly double the weight loss compared to liraglutide.

Side-by-side comparison diagram of Semaglutide and Liraglutide mechanisms of action
Conceptual comparison — not to scale

Head-to-Head Comparison

CriteriaSemaglutideLiraglutide
Primary mechanismGLP-1 receptor agonist (94% homology to native GLP-1)GLP-1 receptor agonist (97% homology to native GLP-1)
Best forAdult weight loss, type 2 diabetes, cardiovascular risk reductionPediatric obesity (ages 12+), patients wanting a proven first-generation GLP-1
Route of administrationOnce-weekly subcutaneous injection or once-daily oral tabletOnce-daily subcutaneous injection
Typical dosage0.25 mg escalating to 2.4 mg weekly (Wegovy) or 7–14 mg oral daily (Rybelsus)0.6 mg escalating to 3.0 mg daily (Saxenda)
Average weight loss~15.8% at 68 weeks (STEP 8 head-to-head trial)~6.4% at 68 weeks (STEP 8 head-to-head trial)
Half-life~7 days (enables weekly dosing)~13 hours (requires daily dosing)
Injection frequencyOnce weekly (4 injections/month) or daily oralOnce daily (30 injections/month)
FDA statusApproved: Wegovy (obesity, 2021), Ozempic (T2D, 2017), Rybelsus (oral, T2D, 2019)Approved: Saxenda (obesity, 2014), Victoza (T2D, 2010)
Cardiovascular outcomesSELECT trial: 20% MACE reduction in overweight/obese adultsLEADER trial: 13% MACE reduction in T2D patients
Side effectsNausea (44%), vomiting (24%), diarrhea (30%) — side effects more intense at higher efficacyNausea (39%), vomiting (16%), diarrhea (21%) — generally milder GI profile
Generic/biosimilar availabilityNo generics available — patent protection through late 2030sApproaching patent expiry — biosimilars expected in coming years
Approximate monthly cost (US list price)$1,350–$1,430/month (Wegovy)$1,350–$1,400/month (Saxenda)

When to Choose Each

Choose Semaglutide

Adults seeking best-in-class single GLP-1 efficacy, patients with cardiovascular disease, anyone preferring weekly injections or oral dosing, first-line treatment for obesity and T2D

Choose Liraglutide

Adolescents aged 12–17, patients wanting the mildest GLP-1 introduction, cost-sensitive patients once biosimilars arrive, or those who did not tolerate semaglutide's more intense side effects

Verdict

Semaglutide is the clear upgrade over liraglutide for most patients. The STEP 8 head-to-head trial demonstrated semaglutide produced 15.8% weight loss versus liraglutide's 6.4% — nearly 2.5 times more effective — with the added convenience of weekly rather than daily injections. Semaglutide also has stronger cardiovascular outcomes data (20% vs 13% MACE reduction). Liraglutide remains valuable for adolescents aged 12+, as a lower-intensity starting option, and will become more accessible as biosimilars arrive. For adult patients choosing between the two, semaglutide is the superior choice by every major clinical measure.

References

  1. Semaglutide 2.4 mg vs liraglutide 3.0 mg for weight management (STEP 8): a head-to-head randomised trial (2022) — PubMed
  2. Once-weekly semaglutide in adults with overweight or obesity (STEP 1) (2021) — PubMed
  3. Liraglutide and cardiovascular outcomes in type 2 diabetes (LEADER) (2016) — PubMed
  4. Semaglutide and cardiovascular outcomes in patients with overweight or obesity (SELECT) (2023) — PubMed

Frequently Asked Questions

How does the STEP 8 head-to-head trial compare semaglutide and liraglutide?
STEP 8 was a 68-week randomized controlled trial directly comparing semaglutide 2.4 mg weekly to liraglutide 3.0 mg daily in adults with obesity. Semaglutide produced 15.8% mean weight loss versus 6.4% for liraglutide. Notably, 70.9% of semaglutide patients lost at least 10% body weight compared to just 25.6% of liraglutide patients. GI side effects were somewhat more common with semaglutide but generally manageable.
Is liraglutide safer than semaglutide since it has been available longer?
Liraglutide has the longest post-marketing safety record of any GLP-1 agonist (since 2010), which provides reassurance. However, semaglutide now also has extensive real-world safety data since its 2017 launch, plus the large SELECT cardiovascular outcomes trial. Both drugs share the same class-level safety considerations (GI effects, rare pancreatitis risk, thyroid C-cell warnings in animal models). Neither has shown significant unexpected safety signals with long-term use.
Both are made by Novo Nordisk — what is structurally different about semaglutide?
Semaglutide has three key modifications compared to liraglutide: a C-18 fatty diacid chain (vs C-16 in liraglutide) that provides stronger albumin binding, an amino acid substitution at position 8 (Aib) that increases resistance to DPP-4 enzymatic degradation, and an amino acid substitution at position 34. These changes extend the half-life from ~13 hours to ~7 days, enabling once-weekly dosing and achieving higher sustained receptor occupancy.
Can I take semaglutide orally instead of injecting?
Yes — Rybelsus (oral semaglutide) is FDA-approved for type 2 diabetes at 7 mg or 14 mg daily doses. It uses the SNAC absorption enhancer to survive gastric acid. However, oral semaglutide is not currently approved specifically for weight loss (only injectable Wegovy has the obesity indication), and oral bioavailability is only ~1%, requiring much larger doses. High-dose oral semaglutide (25 mg and 50 mg) for obesity is in late-stage development.
Do semaglutide and liraglutide have the same side effects?
Both belong to the GLP-1 receptor agonist class and share the same core side effect profile: nausea, vomiting, diarrhea, and constipation, primarily during dose escalation. Research from the STEP 8 head-to-head trial indicates that semaglutide tends to produce somewhat higher rates of GI side effects compared to liraglutide, likely due to stronger receptor activation. However, semaglutide's longer half-life means side effects are more sustained once they occur, while liraglutide's 13-hour half-life allows faster resolution. Both carry the same class-level warnings regarding pancreatitis risk and thyroid C-cell tumors observed in animal models. Consulting a healthcare provider about managing side effects during titration is recommended.

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