Suplmnt

Tirzepatide vs Semaglutide

Evidence Level: robust

For maximum weight loss or faster inches off the waist, choose tirzepatide. If you have established cardiovascular disease and want proven event reduction—or prefer an oral option for diabetes—choose semaglutide. [1][2][3][4][5]

Both are highly effective incretin therapies. Head-to-head and network data show tirzepatide yields greater weight and A1C reductions, often with similar overall tolerability. Semaglutide uniquely has randomized evidence of lower cardiovascular events in people with obesity and established CVD, plus an oral form for T2D. Coverage, access programs, and individual risk factors (gallbladder disease history, retinopathy in diabetics, anesthesia plans) should guide the final choice. [1][2][3][6][7][8]

Tirzepatide (Zepbound/Mounjaro) Products

Semaglutide (Wegovy/Ozempic/Rybelsus) Products

The Comparison

A Tirzepatide (Zepbound/Mounjaro)

by Zepbound (obesity/OSA); Mounjaro (T2D)

Standardization: Single active peptide; dual GIP/GLP‑1 receptor agonist

Dosage: Start 2.5 mg weekly ×4 weeks, then 5→7.5→10→12.5→15 mg as tolerated; maintenance 5–15 mg weekly

Benefits

  • •Largest average weight loss in class in H2H vs semaglutide
  • •Greater A1C reduction vs semaglutide 1 mg in T2D
  • •HFpEF outcomes and CVOT non-inferior to dulaglutide; renal signals

Drawbacks

  • •GI AEs during titration; potential gallbladder disease and pancreatitis risks
  • •No oral form; CV hard-outcome reduction vs placebo not yet established in obesity

Safety:US boxed warning for thyroid C-cell tumors (rodents). Contraindicated with personal/family MTC or MEN2. Watch for pancreatitis, gallbladder disease, AKI with dehydration, severe GI disease, hypoglycemia when combined with insulin/SU; retinopathy complications reported in T2D.

B Semaglutide (Wegovy/Ozempic/Rybelsus)

by Wegovy (obesity/CV risk, MASH*); Ozempic (T2D); Rybelsus (oral T2D)

Standardization: Single active peptide; GLP‑1 receptor agonist

Dosage: Wegovy: 0.25→0.5→1.0→1.7→2.4 mg weekly; Ozempic max 2 mg weekly; Rybelsus 7–14 mg daily (empty stomach, ≤120 mL water, wait ≥30 min)

Benefits

  • •Proven 20% MACE reduction in SELECT for obesity with established CVD
  • •Oral option (Rybelsus) for needle-averse T2D
  • •Broad availability and established use

Drawbacks

  • •Less weight loss than tirzepatide at currently approved doses
  • •Oral form has <1% bioavailability and strict fasting rules

Safety:Same boxed warning and precautions as class: MTC/MEN2 contraindication; pancreatitis, gallbladder disease, AKI with dehydration, GI AEs; retinopathy complication signal in diabetics; observational signals about rare eye events are investigational.

Head-to-Head Analysis

Efficacy: weight loss (adults without diabetes) Critical

Winner:Tirzepatide (Zepbound/Mounjaro)• Importance: high

SURMOUNT-5 head-to-head: −20.2% with tirzepatide vs −13.7% with semaglutide at 72 weeks; more patients reached ≥15–25% loss. Network/meta-analyses echo greater loss with tirzepatide. [1][2][3][20][24]

Glycemic control (type 2 diabetes) Critical

Winner:Tirzepatide (Zepbound/Mounjaro)• Importance: high

SURPASS-2: tirzepatide 5–15 mg reduced A1C and weight more than semaglutide 1 mg over 40 weeks; multiple NMAs show larger A1C drops with tirzepatide. [4][21][25]

Cardiovascular outcomes evidence Critical

Winner:Semaglutide (Wegovy/Ozempic/Rybelsus)• Importance: high

SELECT: semaglutide 2.4 mg reduced MACE by 20% vs placebo in obesity without diabetes. Tirzepatide's SURPASS-CVOT showed non-inferiority vs dulaglutide (not superiority vs placebo); HFpEF data are promising but not a broad CVOT win yet. [6][7][8][18][19]

Onset and time‑to‑effect

Winner:Tirzepatide (Zepbound/Mounjaro)• Importance: medium

Real-world and trial curves show larger early weight and A1C deltas with tirzepatide during escalation; SURMOUNT-5 and comparative analyses show higher odds of ≥10–15% loss earlier. [1][24]

Side effects/tolerability Critical

Winner:Tie• Importance: high

GI AEs common for both during titration. Some meta-analyses suggest higher overall GI AE rates with higher-dose tirzepatide; semaglutide shows more gallbladder events in some analyses. Discontinuations in SURMOUNT-5 were numerically higher with semaglutide. [1][22][23]

Formulations and convenience

Winner:Semaglutide (Wegovy/Ozempic/Rybelsus)• Importance: medium

Semaglutide offers an oral option (Rybelsus) though with strict fasting and ~0.8% bioavailability; both have weekly injections. Tirzepatide has no oral form. [10][11][12]

Cost/value and access (U.S.)

Winner:Tie• Importance: medium

List prices are high for both; manufacturers offer direct self-pay vial programs around $499/month (Zepbound) and similar cash offers for Wegovy via NovoCare. Coverage varies by plan/formulary. [14][15][16]

Standardization/quality

Winner:Tie• Importance: medium

Both are FDA-approved biologic peptide drugs with fixed-dose pens/vials and rigorous QC; avoid compounded or "research" semaglutide/tirzepatide due to FDA warnings. [9]

Which Should You Choose?

Maximize weight loss with body‑composition focus

Choose: Tirzepatide (Zepbound/Mounjaro)

Produces greater average and high-threshold weight loss and larger waist reductions vs semaglutide. Consider resistance training and protein to mitigate lean loss. [1][2]

Established cardiovascular disease (no diabetes) seeking event reduction

Choose: Semaglutide (Wegovy/Ozempic/Rybelsus)

Only semaglutide 2.4 mg has RCT evidence reducing MACE in this population to date. [6][7]

Needle‑averse T2D patient prioritizing oral therapy

Choose: Semaglutide (Wegovy/Ozempic/Rybelsus)

Rybelsus provides an oral GLP-1 option (with strict dosing rules). [11][12]

Faster glucose and weight improvements in T2D on metformin

Choose: Tirzepatide (Zepbound/Mounjaro)

Greater A1C and weight reductions vs semaglutide 1 mg in SURPASS-2. [4]

T2D with high retinopathy risk or recent progression

Choose: Either option

Both labels caution on retinopathy in diabetics; semaglutide has specific signal (SUSTAIN-6); decision should individualize with eye care input. [17][13]

Safety Considerations

Do not use either drug with personal/family history of medullary thyroid carcinoma or MEN2 (boxed warning). Monitor for severe abdominal pain—evaluate for pancreatitis. Watch for gallbladder disease (cholelithiasis/cholecystitis) if RUQ pain occurs. Titrate slowly to reduce GI AEs; pause escalation during illness or if AEs troublesome. In T2D, retinopathy may transiently worsen with rapid glycemic improvement; coordinate eye exams. Risk of hypoglycemia increases with insulin/sulfonylureas—consider dose reductions. Dehydration can precipitate AKI—maintain fluids. Hold before anesthesia due to aspiration risk per label warnings. Avoid compounded or "research-only" versions; use FDA-approved products. [5][13][17][9]

Common Questions

Which leads to more weight loss on average?

Tirzepatide. In the head-to-head SURMOUNT-5 trial it produced −20.2% vs −13.7% with semaglutide at 72 weeks. [1][2]

Which has proven cardiovascular event reduction for obesity without diabetes?

Semaglutide 2.4 mg (Wegovy) reduced MACE by 20% in SELECT. [6][7]

Is there an oral option?

Yes—semaglutide (Rybelsus) 7–14 mg daily, but take on an empty stomach with ≤120 mL water and wait ≥30 minutes; bioavailability is ~0.8%. [11][12]

Are side effects different?

Both cause GI effects; gallbladder events occur with GLP-1s. Some analyses show higher overall GI AEs at higher tirzepatide doses; discontinuations were similar in H2H. [1][22][23]

How much do they cost without insurance?

Manufacturers offer self-pay programs around $499/month for Zepbound vials and a $499 Wegovy cash option via NovoCare; usual list prices are higher. [14][15][16]

Sources

  1. 1.
    SURMOUNT‑5 NEJM head‑to‑head (tirzepatide vs semaglutide) and summaries (2025) [link]
  2. 2.
    ACC Journal Scan of SURMOUNT‑5 (2025) [link]
  3. 3.
    Weill Cornell news on SURMOUNT‑5 (2025) [link]
  4. 4.
    SURPASS‑2 NEJM (T2D: tirzepatide vs semaglutide 1 mg) (2021) [link]
  5. 5.
    Zepbound Prescribing Information (Drugs.com PI extract) (2025) [link]
  6. 6.
    SELECT trial NEJM (semaglutide 2.4 mg reduces MACE) (2023) [link]
  7. 7.
    ACC SELECT trial overview (2023) [link]
  8. 8.
    SURPASS‑CVOT topline (tirzepatide non‑inferior vs dulaglutide) (2025) [link]
  9. 9.
    FDA actions vs unapproved online GLP‑1s (2024) [link]
  10. 10.
    Wegovy Prescribing Information (Drugs.com PI extract) (2025) [link]
  11. 11.
    Rybelsus Prescribing Information (patient PI) (2025) [link]
  12. 12.
    Oral semaglutide bioavailability ~0.8% (clinical PK) (2021) [link]
  13. 13.
    Semaglutide eye safety signals (NAION) – observational (2024) [link]
  14. 14.
    Zepbound direct self‑pay pricing (2025) [link]
  15. 15.
    All Zepbound vial doses ≤$499/month via LillyDirect (2025) [link]
  16. 16.
    Wegovy cash‑pay $499 via NovoCare (DTC pharmacy) (2025) [link]
  17. 17.
    Labels—class warnings incl. retinopathy (tirzepatide) (2025) [link]
  18. 18.
    HFpEF outcomes press (tirzepatide) (2025) [link]
  19. 19.
    AHA newsroom on tirzepatide in HFpEF (2025) [link]
  20. 20.
    American College of Cardiology scan and AP coverage of SURMOUNT‑5 (2025) [link]
  21. 21.
    NMA (T2D): tirzepatide vs semaglutide (2024) [link]
  22. 22.
    GI safety meta‑analysis (obesity without diabetes) (2025) [link]
  23. 23.
    FDA Zepbound approval notice and safety summary (2023) [link]
  24. 24.
    Scoping review of GLP‑1 RA NMAs (tirzepatide vs semaglutide) (2024) [link]
  25. 25.
    Indirect comparison article (summary) (2023) [link]

Tirzepatide (Zepbound/Mounjaro) vs Semaglutide (Wegovy/Ozempic/Rybelsus) • 25 sources

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