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Head-to-Head — GLP-1 Class

Semaglutide vs Tirzepatide FDA Approved

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Wegovy / Ozempic vs Zepbound / Mounjaro  |  GLP-1 monotherapy vs dual GIP/GLP-1  |  The SURMOUNT-5 comparison
The Gist

Tirzepatide wins on weight loss. SURMOUNT-5 (NEJM, May 11, 2025; 751 participants, 72 weeks) put them head-to-head at maximum tolerated doses and found tirzepatide produced −20.2% weight loss vs −13.7% for semaglutide (P<0.001), with −18.4 cm vs −13.0 cm waist reduction (Aronne et al., 2025).
Semaglutide has the placebo-controlled cardiovascular trial. In SELECT (n = 17,604), adults with cardiovascular disease and overweight or obesity but no diabetes had 20% fewer major cardiovascular events on semaglutide than on placebo (HR 0.80; Lincoff et al., 2023); cardiovascular death alone was not significantly lower (HR 0.85; Wegovy label). SURPASS-CVOT showed tirzepatide noninferior to dulaglutide on 3-point MACE in T2D+ASCVD, an active-comparator design (Nicholls et al., 2025); it is the basis of a 2026 Mounjaro indication to reduce cardiovascular events in type 2 diabetes (Mounjaro label).
Most stomach side effects were about as common on both. In SURMOUNT-5's posted results, nausea (43.6% on tirzepatide vs 44.4% on semaglutide), diarrhea and constipation were about as common on both drugs, while vomiting (15.0% vs 21.3%) was reported less often on tirzepatide (ClinicalTrials.gov NCT05822830).

Side-by-Side Quick Facts

Semaglutide
Ozempic / Wegovy / Rybelsus / NovoCare pill
Class
GLP-1 receptor agonist (monotherapy)
MW
4,113 Da
Half-life
~7 days
Route
SubQ weekly (Ozempic/Wegovy) or oral daily (Rybelsus/Wegovy pill)
Max dose (obesity)
7.2 mg weekly by injection in adults (maintenance 1.7 or 2.4 mg); 25 mg daily as tablets (Wegovy label)
FDA approvals
Ozempic (T2D) 2017; Wegovy (obesity) Jun 2021; CV indication 2024; Wegovy pill Dec 2025
Pivotal obesity trial
STEP 1 — 14.9% weight loss at 68 weeks
CV outcomes
SELECT: 20% MACE reduction vs placebo in non-diabetic CVD
Tirzepatide
Mounjaro / Zepbound
Class
Dual GIP + GLP-1 receptor agonist
MW
4,813 Da
Half-life
~5 days
Route
SubQ weekly
Max dose (obesity)
15 mg weekly (Zepbound label)
FDA approvals
Mounjaro (T2D) May 2022; Zepbound (obesity) Nov 2023; OSA (moderate-severe with obesity) Dec 2024; Mounjaro CV risk reduction in T2D Aug 2026 (Drugs@FDA)
Pivotal obesity trial
SURMOUNT-1 — up to 22.5% weight loss at 72 weeks
CV outcomes
SURPASS-CVOT: noninferior to dulaglutide (not superior) on 3-point MACE in T2D+ASCVD

The SURMOUNT-5 Head-to-Head Trial

SURMOUNT-5 (Aronne LJ et al., N Engl J Med 2025;393(1):26-36, published online May 11, 2025; NCT05822830) is the first and only randomized head-to-head trial of tirzepatide vs semaglutide at their maximum tolerated doses in obese, non-diabetic adults.

  • Design — Phase 3b, open-label, 1:1 randomization to tirzepatide (10 mg or 15 mg) vs semaglutide (1.7 mg or 2.4 mg) SubQ weekly for 72 weeks, each at the maximum tolerated dose, in adults with obesity but without type 2 diabetes (Aronne et al., 2025). Conducted at 32 sites across the U.S. and Puerto Rico from April 2023 to November 2024 (ClinicalTrials.gov NCT05822830).
  • Population — 751 adults with BMI ≥ 30 kg/m² (or ≥ 27 plus one obesity-related complication) and no diabetes. Mean age 45, majority female.
  • Primary endpoint — body weight change at week 72 — Tirzepatide −20.2% (95% CI −21.4 to −19.1) vs semaglutide −13.7% (95% CI −14.9 to −12.6). P < 0.001. Absolute between-arm difference: 6.5 percentage points in favour of tirzepatide.
  • Waist circumference — Tirzepatide −18.4 cm vs semaglutide −13.0 cm (P < 0.001).
  • Proportion reaching ≥ 25% weight loss — Participants on tirzepatide were more likely to lose at least 10%, 15%, 20% and 25% of their weight, all key secondary end points (Aronne et al., 2025). Lilly's topline announcement of December 4, 2024 gave 31.6% on tirzepatide vs 16.1% on semaglutide for at least 25%.
  • Adverse-event discontinuation — Overall drug discontinuation for AE: 6.1% tirzepatide vs 8.0% semaglutide. GI-specific: 2.7% tirzepatide vs 5.6% semaglutide. Serious AEs 4.8% vs 3.5%. No deaths in either arm.
  • Body composition — Tirzepatide produced larger absolute reductions in both total fat mass and abdominal/visceral fat as assessed by waist circumference. Lean-mass loss proportional to total weight change was broadly similar between the two drugs, consistent with earlier SURMOUNT and STEP body-composition subsets — neither agent produced disproportionate lean-mass loss relative to the expected body-composition curve.
  • Cardiometabolic secondaries — Tirzepatide produced larger reductions in systolic and diastolic blood pressure, fasting glucose, HbA1c (despite the nondiabetic population), triglycerides, and hsCRP. The direction of effect favoured tirzepatide across nearly all cardiometabolic endpoints reported in the SURMOUNT-5 publication, though the trial was not powered for hard cardiovascular outcomes.
  • Subgroup analyses — Per the protocol-specified subgroups, the tirzepatide advantage was directionally consistent across baseline-BMI strata (30 to < 35, 35 to < 40, ≥ 40 kg/m²), age categories, sex, and race/ethnicity. No subgroup reversed the direction of effect; absolute magnitudes of difference were largest in the highest BMI strata — consistent with both drugs producing percentage-based weight loss with a larger absolute floor at higher starting weights.
  • Non-GI adverse events — Injection-site reactions were reported in 8.6% on tirzepatide vs 0.3% on semaglutide; reflux (6.1% vs 10.6%) and upper respiratory tract infections (8.6% vs 11.4%) were reported less often on tirzepatide. Serious gallbladder and pancreas events were few in both groups (ClinicalTrials.gov NCT05822830).
  • Post-hoc 10-year CVD projection — A subsequent SURMOUNT-5 post-hoc analysis (Mamas MA et al., Eur Heart J Open 2025;5(5):oeaf117) applied population-risk-equation modelling to the observed weight reductions and projected that 72 weeks of tirzepatide treatment would prevent roughly 2 million cardiovascular events over 10 years in a U.S. treatment-eligible primary-prevention population, versus ~1.15 million with semaglutide. This is modelled risk, not observed outcome, but it illustrates the downstream cardiometabolic magnitude of the observed weight-loss gap in a population context.

The open-label design is the main limitation — expectation effects cannot be excluded — but the magnitude of separation (6.5 percentage points), the consistency across secondary endpoints and the directional consistency across every prespecified subgroup make the efficacy signal difficult to explain on expectation alone.

Cardiovascular Outcomes — SELECT vs SURPASS-CVOT

The cardiovascular evidence base for the two is different in design and therefore different in what it tells a prescriber.

SELECT (semaglutide)SURPASS-CVOT (tirzepatide)
ComparatorPlaceboDulaglutide (1.5 mg, active)
PopulationNon-diabetic, overweight/obese, preexisting CVD (n = 17,604)Type-2 diabetic with atherosclerotic CVD (n = 13,299)
Follow-upMean 39.8 months (Lincoff et al., 2023)Median ~4 years
Primary endpoint3-point MACE: CV death / nonfatal MI / nonfatal stroke3-point MACE: CV death / MI / stroke
Result6.5% semaglutide vs 8.0% placebo. HR 0.80 (0.72–0.90). Superior (P < 0.001).12.2% tirzepatide vs 13.1% dulaglutide. Noninferior (P = 0.003) but not superior (P = 0.09). Expanded 4-point MACE (adds coronary revascularization) HR 0.88 (0.80–0.96).
What it provesSemaglutide prevents cardiovascular events in people without diabetes who have existing CVDTirzepatide is at least as good as dulaglutide (an already-proven CV-benefit GLP-1) — but the data do not include a placebo-controlled trial

Semaglutide's cardiovascular evidence includes a placebo-controlled outcome trial in people without diabetes (Lincoff et al., 2023), the basis of Wegovy's indication to reduce major cardiovascular events in adults with cardiovascular disease and obesity or overweight (Wegovy label). Tirzepatide's rests on noninferiority to dulaglutide, a drug already shown to lower cardiovascular events (Nicholls et al., 2025); in August 2026 that trial became the basis of a Mounjaro indication to reduce major cardiovascular events in adults with type 2 diabetes at high risk for them (Mounjaro label).

Side Effects & Tolerability

Important

Like any medication, potential risks exist. This section summarizes what the literature reports — always consult a licensed healthcare provider before use.

In SURMOUNT-5, which compared the two at their maximum tolerated doses, the most common side effects of both were gastrointestinal, mostly mild to moderate and mainly during dose escalation (Aronne et al., 2025). The table gives the rates in the trial's posted results, among the 750 participants who took at least one dose (ClinicalTrials.gov NCT05822830).

Adverse eventSemaglutide (n = 376)Tirzepatide (n = 374)
Nausea44.4%43.6%
Diarrhea23.4%23.5%
Constipation28.5%27.0%
Vomiting21.3%15.0%
GERD / reflux10.6%6.1%
Injection-site reaction0.3%8.6%
Serious AEs3.5%4.8%
Deaths00

In those results, vomiting and reflux were reported less often on tirzepatide, and injection-site reactions and serious adverse events more often (ClinicalTrials.gov NCT05822830). The Wegovy, Zepbound and Mounjaro labels each carry a boxed warning for thyroid C-cell tumors, which semaglutide and tirzepatide caused in rodents (whether they do in humans is unknown), and a separate warning for pancreatitis; both drugs are contraindicated with a personal or family history of medullary thyroid carcinoma or with MEN 2 (Wegovy, Zepbound and Mounjaro labels).

Real-World vs Trial Data

Large-scale retrospective analyses of electronic health records and pharmacy claims have consistently shown smaller average weight-loss effects in routine clinical practice than the double-digit percentages reported in SURMOUNT-5, SURMOUNT-1, and STEP 1. The authors of one health-system study judged the gap likely due to higher rates of stopping and lower maintenance doses than in the trials (Gasoyan et al., Obesity, Sep 2025).

  • Rodriguez et al. (Truveta, JAMA Intern Med 2024) — Retrospective propensity-score-matched cohort of 18,386 adults with overweight or obesity initiating tirzepatide or semaglutide labelled for T2D (on- and off-label use) between May 2022 and September 2023. Tirzepatide was associated with significantly greater weight loss than semaglutide, with direction of effect consistent with the SURMOUNT-5 head-to-head. More than half of patients discontinued within the study period — a real-world persistence rate much lower than in randomised trials.
  • Gasoyan et al. (Cleveland Clinic, Obesity 2025) — Retrospective cohort of 7,881 adults initiating semaglutide or tirzepatide for obesity (no T2D) at a large integrated health system across Ohio and Florida. Average 1-year weight loss was substantially below trial benchmarks for both drugs when the full intention-to-treat population was analysed. Among the 967 patients who stayed on treatment at a high maintenance dose for the year, weight fell 13.7% with semaglutide and 18.0% with tirzepatide, which the authors call comparable to STEP 1 (14.9%) and SURMOUNT-1 (15.0–20.9%) (Gasoyan et al., Obesity, Sep 2025).
  • Staying on treatment — In the Cleveland Clinic cohort, mean weight loss at one year was 3.6% in people who stopped within 3 months, 6.8% in those who stopped at 3–12 months and 11.9% in those who did not stop (Gasoyan et al., Obesity, Sep 2025). A second study from the same health system took a random sample of 288 adults without type 2 diabetes who stopped within the first year: 47.6% stopped because of cost or insurance problems, 14.6% because of side effects, 11.8% because of shortages and 1.7% because of too little weight loss (Gasoyan et al., Obesity, Dec 2025).
  • Post-discontinuation trajectory — The STEP 1 extension (Wilding et al. 2022) reported that participants regained roughly two-thirds of their trial-achieved weight loss within 12 months of stopping semaglutide, with parallel partial reversal of cardiometabolic gains. SURMOUNT-4 (Aronne et al., JAMA 2024) reproduced the pattern with tirzepatide — the placebo-after-lead-in arm regained a large fraction of their initial loss over 52 weeks — and a post-hoc analysis identified ≥ 25% weight regain within 1 year in the majority of withdrawn participants, with reversal of initial cardiometabolic improvements proportional to the regain. Real-world post-discontinuation trajectories appear more heterogeneous than the clean trial curves — Gasoyan et al. reported that a non-trivial fraction of patients retained meaningful weight loss after stopping — but on average the trial regain-pattern holds.

Switching Between Them

No randomized trial of switching between the two is registered on ClinicalTrials.gov, and neither the Wegovy nor the Zepbound label gives a dose for switching from the other drug.

  • Tirzepatide after semaglutide — The Zepbound label starts every patient at 2.5 mg weekly for 4 weeks; 2.5 mg is a starting dose only (Zepbound label). In a single-arm study, 152 adults with type 2 diabetes on a stable GLP-1 receptor agonist (55% on semaglutide, most often 1.0 mg) switched straight to tirzepatide 5 mg weekly: over 12 weeks HbA1c fell 0.43 points and weight 2.15 kg, 13.2% had gastrointestinal adverse events and 2% stopped tirzepatide because of adverse events (Jabbour et al., 2024; ClinicalTrials.gov NCT05706506). Some clinic protocols describe starting tirzepatide at 5 or 7.5 mg after semaglutide 2.4 mg; no randomized trial has compared these approaches.
  • Semaglutide after tirzepatide — The Wegovy label starts injections at 0.25 mg weekly and tablets at 1.5 mg daily, and its only switching steps are between Wegovy injection and Wegovy tablets (Wegovy label).
  • Half-lives — Semaglutide's elimination half-life is about 1 week, and it stays in the circulation for about 5 to 7 weeks after the last dose; tirzepatide's is about 5 days (Wegovy and Zepbound labels).
  • Combining the two — Both labels list use with any other GLP-1 receptor agonist as not recommended, and tirzepatide is itself a GIP and GLP-1 receptor agonist (Wegovy and Zepbound labels).

Cost Comparison — April 2026

The pricing landscape has changed substantially since the original FDA-approved list prices. Eli Lilly launched LillyDirect (single-dose vials, direct-to-consumer) in 2024 and cut prices on December 1, 2025. Novo Nordisk launched the Wegovy oral pill in January 2026 with NovoCare self-pay pricing starting at $149/month. FDA determined the tirzepatide shortage resolved (October 2024, reaffirmed December 19, 2024) and the semaglutide shortage resolved (February 21, 2025). Its grace periods for compounders then ended between February and May 2025 (tirzepatide: March 5 for 503A pharmacies, March 19 for outsourcing facilities; semaglutide: April 24 and May 22), so pharmacy-compounded GLP-1s are no longer broadly available except in narrow, individualized clinical-need scenarios.

ChannelSemaglutideTirzepatide
Manufacturer list (brand)Wegovy ~$1,349 / month (4 pens)Zepbound ~$1,060 / month (4 pens)
Direct-to-consumer (vials / pill)NovoCare — Wegovy pill from $149 / mo (self-pay); injection $499 and upLillyDirect vials — $299 (2.5 mg) / $399 (5 mg) / $449 (7.5 mg+) / mo
Commercial insurance (with coverage)$25–$50 / mo copay on savings card$25–$50 / mo copay on savings card
MedicareLimited — T2D indication covered; obesity not covered under Part D except via new Medicare Bridge program (July 2026)Medicare Bridge (July 2026): $50 / mo for KwikPen in BMI ≥ 35 or ≥ 27 + comorbidities
Compounded (historical)Historically $200–$400 / mo; FDA’s grace period ended April–May 2025Historically $250–$500 / mo; FDA’s grace period ended March 2025

Pricing varies by dose, pharmacy, insurance plan, and jurisdiction, and the figures above may be out of date.

Where the Evidence Differs

QuestionWhere the evidence pointsWhat the evidence is
More weight lossTirzepatideSURMOUNT-5: 20.2% vs 13.7% at 72 weeks at maximum tolerated doses, in 751 adults with obesity without diabetes (Aronne et al., 2025)
Fewer cardiovascular events than placebo, without diabetesSemaglutideSELECT: 6.5% vs 8.0% had a cardiovascular death, heart attack or stroke (HR 0.80) among 17,604 adults with cardiovascular disease and overweight or obesity (Lincoff et al., 2023); Wegovy carries an indication for it (Wegovy label)
Gastrointestinal side effectsSimilar; vomiting and reflux less often on tirzepatideSURMOUNT-5 posted results: nausea 43.6% vs 44.4%, vomiting 15.0% vs 21.3%, reflux 6.1% vs 10.6% (ClinicalTrials.gov NCT05822830)
Longer time on the marketSemaglutideFirst approved in December 2017 as Ozempic; tirzepatide in May 2022 as Mounjaro (Drugs@FDA)
Moderate-severe OSA with obesityTirzepatideFDA-approved indication for Zepbound since December 2024 (Drugs@FDA; Zepbound label), from SURMOUNT-OSA (Malhotra et al., 2024)
Oral formSemaglutideRybelsus tablets for type 2 diabetes since 2019 and Wegovy tablets since December 2025 (Drugs@FDA); tirzepatide is injection only (Zepbound label)
T2D with established ASCVDBoth have outcome dataSUSTAIN-6: fewer major cardiovascular events than placebo (HR 0.74) in 3,297 adults with type 2 diabetes at high cardiovascular risk (Marso et al., 2016). SURPASS-CVOT: tirzepatide noninferior to dulaglutide in 13,299 adults with type 2 diabetes and atherosclerotic disease (Nicholls et al., 2025), the basis of Mounjaro's 2026 indication to reduce major cardiovascular events (Mounjaro label)
Heart failure with preserved EF + obesityBoth have trialsSTEP-HFpEF: semaglutide improved symptoms, physical limits and walking distance over 52 weeks in 529 patients (Kosiborod et al., 2023). SUMMIT: tirzepatide lowered the risk of cardiovascular death or worsening heart failure (HR 0.62) and improved symptoms in 731 patients (Packer et al., 2025)

Regulatory Status

Current Status — April 2026

Semaglutide — FDA-approved as Ozempic (T2D, 2017), Rybelsus (oral T2D, 2019), Wegovy (chronic weight management, June 2021), with CV risk-reduction indication in 2024 based on SELECT and oral Wegovy approved December 2025.

Tirzepatide — FDA-approved as Mounjaro (T2D, May 2022) and Zepbound (chronic weight management, November 2023; moderate-severe OSA with obesity, December 2024).

Both have Boxed Warnings regarding thyroid C-cell tumors (based on rodent carcinogenicity studies) and contraindications in personal or family history of medullary thyroid carcinoma or MEN-2 syndrome. Both carry warnings for pancreatitis, gallbladder disease, hypoglycemia with concurrent insulin/sulfonylurea, diabetic retinopathy complications, and acute kidney injury.

Cost & Access

Both are FDA-approved branded medications available by prescription through retail pharmacies, manufacturer direct-to-consumer programs (NovoCare, LillyDirect), and — where covered — through commercial and government insurance.

Insurance reality. Commercial coverage for the obesity indications (Wegovy, Zepbound) almost always requires prior authorization. Coverage for the T2D labels (Ozempic, Mounjaro) is generally broader and less restrictive because the regulatory indication is long-established. Medicare Part D has historically excluded obesity indications; the new Medicare Bridge program (announced for mid-2026 rollout) is expected to provide limited coverage for BMI ≥ 35 or ≥ 27 with comorbidities. Medicaid coverage varies substantially by state. Compounded GLP-1s are cash-pay only and are never reimbursed by insurance.

Compounded status. Compounded GLP-1 preparations are largely no longer available from 503A or 503B compounding pharmacies as of 2025 outside narrow individual clinical-need situations. FDA, not the manufacturers, determined the shortages resolved (tirzepatide December 19, 2024; semaglutide February 21, 2025), and its enforcement discretion for compounders ended between February and May 2025. Any remaining compounded supply lives in limited, individually-justified scenarios rather than the broad telehealth channels that were active until then. In one health system's records, cost or insurance problems were the most common reason people stopped semaglutide or tirzepatide in their first year (47.6% of 288) (Gasoyan et al., Obesity, Dec 2025).

Kalios does not sell compounds. Current prices are set by the manufacturer programs and insurers and vary by jurisdiction.

Frequently Asked Questions

Which has better cardiovascular benefit?

Semaglutide has completed placebo-controlled trials of major cardiovascular events; tirzepatide's completed outcome trial used an active comparator. SELECT (NEJM 2023, n = 17,604) found 20% fewer cardiovascular deaths, heart attacks and strokes combined on semaglutide than on placebo in adults with cardiovascular disease and overweight or obesity but no diabetes (HR 0.80; Lincoff et al., 2023); cardiovascular death alone was not significantly lower (HR 0.85, 95% CI 0.71–1.01; Wegovy label). SURPASS-CVOT (NEJM 2025) showed tirzepatide noninferior to dulaglutide — an active comparator shown to lower cardiovascular events — but did not meet superiority on the 3-point MACE primary endpoint (HR 0.92, 95.3% CI 0.83–1.01, P = 0.09 for superiority) (Nicholls et al., 2025). All-cause death was lower on tirzepatide (HR 0.84, 95% CI 0.75–0.94), a result the label marks as not controlled for multiple testing, and in August 2026 the Mounjaro label added an indication to reduce major cardiovascular events in adults with type 2 diabetes at high risk for them (Mounjaro label).

Is compounded the same as brand-name?

No. Compounded drugs are not FDA approved: FDA does not review them for safety, effectiveness or quality before they are sold. FDA reports that some compounded semaglutide was made from salt forms, such as semaglutide sodium and semaglutide acetate, which are different active ingredients from the one in the approved drugs, and that it has received multiple adverse event reports, some requiring hospitalization, that may be related to dosing errors with compounded injectable semaglutide. Enforcement discretion ended in early 2025, after FDA determined the shortages resolved (tirzepatide December 19, 2024; semaglutide February 21, 2025): for tirzepatide on March 5 (503A) and March 19 (outsourcing facilities), for semaglutide on April 24 and May 22. FDA says a compounded drug might be appropriate if a patient's medical need cannot be met by an FDA-approved drug, or the approved drug is not commercially available.

What about use for type 2 diabetes?

Both have FDA-approved type 2 diabetes indications: semaglutide as Ozempic since 2017 and as Rybelsus tablets since 2019, tirzepatide as Mounjaro since 2022 (Drugs@FDA). SURPASS-2 (NEJM 2021) was the dedicated head-to-head in T2D: in 1,879 adults over 40 weeks, all three tirzepatide doses (5, 10 and 15 mg) lowered HbA1c and weight more than semaglutide 1 mg (Frías et al., 2021). SUSTAIN-6 is the semaglutide cardiovascular-outcome trial in T2D with established CVD or high CV risk (Marso et al., 2016); SURPASS-CVOT is the corresponding tirzepatide trial (Nicholls et al., 2025), and in August 2026 the Mounjaro label added an indication to reduce major cardiovascular events in adults with type 2 diabetes at high risk for them (Mounjaro label).

Which has worse GI side effects?

In SURMOUNT-5's posted results, nausea (44.4% on semaglutide vs 43.6% on tirzepatide), diarrhea (23.4% vs 23.5%) and constipation (28.5% vs 27.0%) were about as common on both drugs, while vomiting (21.3% vs 15.0%) and reflux (10.6% vs 6.1%) were reported more often on semaglutide (ClinicalTrials.gov NCT05822830). Most gastrointestinal events were mild to moderate and came mainly during dose escalation (Aronne et al., 2025).

Can I switch mid-treatment?

Neither label gives a dose for switching from the other drug: Zepbound starts at 2.5 mg weekly and Wegovy injections at 0.25 mg weekly (Zepbound and Wegovy labels). No randomized trial has compared ways of switching. In a single-arm study, 152 adults with type 2 diabetes switched from a GLP-1 receptor agonist, most often semaglutide, straight to tirzepatide 5 mg, and 13.2% had gastrointestinal adverse events over 12 weeks (Jabbour et al., 2024). See the Switching Between Them section above.

What happens if I stop taking it?

Trial data show substantial weight regain. The STEP 1 extension (Wilding et al., Diabetes Obes Metab 2022) reported that participants regained roughly two-thirds of their trial-achieved weight loss within 12 months of withdrawal, with parallel partial reversal of cardiometabolic improvements. In SURMOUNT-4 (Aronne et al., JAMA 2024), adults who had lost 20.9% of their weight during a 36-week tirzepatide lead-in and were then switched to placebo saw their weight rise 14.0% over the next 52 weeks; 16.6% of them kept at least 80% of their earlier loss, vs 89.5% of those who stayed on tirzepatide. In one health system's records, weight stayed fairly stable after people stopped, unlike in the trials, and the authors call for study of what else those patients did to manage their weight (Gasoyan et al., Obesity, Sep 2025). The STEP 1 extension's authors concluded that their findings suggest ongoing treatment is needed to keep the improvements (Wilding et al., 2022).

Next Steps

→ Read the full Semaglutide profile →

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Key References

  1. Aronne LJ, Horn DB, le Roux CW, Ho W, Falcon BL, Gomez Valderas E, Das S, Lee CJ, Glass LC, Senyucel C, Dunn JP; SURMOUNT-5 Trial Investigators. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. N Engl J Med. 2025 Jul 3;393(1):26-36. doi: 10.1056/NEJMoa2416394. Epub 2025 May 11. PMID: 40353578. (The SURMOUNT-5 head-to-head — 20.2% vs 13.7% weight loss.)
  2. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. doi: 10.1056/NEJMoa2206038. PMID: 35658024.
  3. Wilding JPH, Batterham RL, Calanna S, et al.; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002. doi: 10.1056/NEJMoa2032183. PMID: 33567185.
  4. Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, Hardt-Lindberg S, Hovingh GK, Kahn SE, Kushner RF, Lingvay I, Oral TK, Michelsen MM, Plutzky J, Tornøe CW, Ryan DH; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023 Dec 14;389(24):2221-2232. doi: 10.1056/NEJMoa2307563. PMID: 37952131.
  5. Nicholls SJ, Pavo I, Bhatt DL, et al.; SURPASS-CVOT Investigators. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes. N Engl J Med. 2025;393(24):2409-2420. doi: 10.1056/NEJMoa2505928. PMID: 41406444.
  6. Marso SP, Bain SC, Consoli A, et al.; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844. doi: 10.1056/NEJMoa1607141. PMID: 27633186.
  7. Husain M, Birkenfeld AL, Donsmark M, et al.; PIONEER 6 Investigators. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2019;381(9):841-851. doi: 10.1056/NEJMoa1901118. PMID: 31185157.
  8. Frías JP, Davies MJ, Rosenstock J, et al.; SURPASS-2 Investigators. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021 Aug 5;385(6):503-515. doi: 10.1056/NEJMoa2107519. PMID: 34170647.
  9. Garvey WT, Frias JP, Jastreboff AM, et al.; SURMOUNT-2 Investigators. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023 Aug 19;402(10402):613-626. PMID: 37385275.
  10. Rubino DM, Greenway FL, Khalid U, et al.; STEP 8 Investigators. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA. 2022 Jan 11;327(2):138-150. PMID: 35015037.
  11. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al.; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023 Sep 21;389(12):1069-1084. PMID: 37622681.
  12. Packer M, Zile MR, Kramer CM, et al.; SUMMIT Trial Study Group. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025 Jan 30;392(5):427-437. PMID: 39555826.
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Checked 4 Oct 2026