Semaglutide vs Tirzepatide: SURMOUNT-5 Head-to-Head Comparison

Side-by-Side Quick Facts

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): 2.4 mg weekly (SubQ Wegovy)
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

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)
FDA approvals: Mounjaro (T2D) May 2022; Zepbound (obesity) Nov 2023; OSA (moderate-severe with obesity) Dec 2024
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 (because of different injection devices and titration schedules), 1:1 randomization to tirzepatide (10 mg or 15 mg) vs semaglutide (1.7 mg or 2.4 mg) SubQ weekly for 72 weeks. Conducted at 32 sites across the U.S. and Puerto Rico from April 2023 to November 2024.
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 — ~32% on tirzepatide vs ~13% on semaglutide.
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.
Weight-loss trajectory — The two curves separated by approximately week 4 and continued to diverge through week 72 without either group reaching a clear plateau. Per NEJM, roughly 64% of tirzepatide participants achieved ≥ 15% weight reduction versus ~40% on semaglutide, and the ≥ 25% threshold was reached by ~32% versus ~13%. Large-magnitude weight loss (≥ 25%) was the category where the gap between the two was widest in absolute terms.
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 — Rates of injection-site reactions, cholelithiasis, pancreatitis, and acute kidney injury were low and numerically similar across the two arms. Both arms showed the small resting-heart-rate increase characteristic of incretin-class agents. There was a numerical signal toward more GERD/reflux on semaglutide and numerically more upper-respiratory symptoms, neither at a magnitude likely to drive prescribing.
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, the directional consistency across every prespecified subgroup, and the early and sustained curve separation 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)
Comparator	Placebo	Dulaglutide (1.5 mg, active)
Population	Non-diabetic, overweight/obese, preexisting CVD (n = 17,604)	Type-2 diabetic with atherosclerotic CVD (n = 13,299)
Follow-up	Median 39.8 months	Median ~4 years
Primary endpoint	3-point MACE: CV death / nonfatal MI / nonfatal stroke	3-point MACE: CV death / MI / stroke
Result	6.5% 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 proves	Semaglutide prevents cardiovascular events in people without diabetes who have existing CVD	Tirzepatide is at least as good as dulaglutide (an already-proven CV-benefit GLP-1) — but the data do not include a placebo-controlled trial

Interpretation for clinical decisions: if reducing MACE in a patient with existing cardiovascular disease is a primary goal, semaglutide currently has the direct placebo-controlled evidence. Tirzepatide's CV evidence rests on noninferiority to a comparator that itself has proven CV benefit — supportive but indirect.

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.

The two share a GLP-1-class adverse event profile dominated by GI symptoms during titration. SURMOUNT-5 is the cleanest apples-to-apples comparison at maximum tolerated doses.

Adverse event	Semaglutide (n = 375)	Tirzepatide (n = 376)
Nausea	~42%	~44%
Diarrhea	~27%	~25%
Constipation	~20%	~17%
Vomiting	~14%	~14%
GERD / reflux	numerically higher	numerically lower
Discontinuation due to GI AEs	5.6%	2.7%
Any drug discontinuation (AE)	8.0%	6.1%
Serious AEs	3.5%	4.8%
Deaths	0	0

The GI-discontinuation gap — roughly 2× fewer dropouts on tirzepatide — is the most reproducible tolerability signal across the SURMOUNT and SURPASS programs, and is the observation that has made tirzepatide the community-preferred option among patients who previously failed semaglutide for tolerability reasons. Both carry class-label boxed warnings for thyroid C-cell tumors (based on rodent data) and pancreatitis. Both are contraindicated in MEN-2 and personal or family history of medullary thyroid carcinoma.

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. This is largely an adherence gap rather than an efficacy gap — the drug appears to do what the trial says, but trial patients take the drug at maintenance dose for the full protocol and real-world patients often do not.

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 patients who remained on high maintenance doses for the full year, outcomes approached trial-like magnitudes: approximately 13.7% weight reduction with semaglutide and 18.0% with tirzepatide — closer to, but still below, STEP 1 (14.9%) and SURMOUNT-1 (up to 22.5%) percentages.
Persistence is the single biggest real-world driver — Across these cohorts, patients who discontinued within 3 months lost minimal weight. Patients who persisted for ≥ 12 months at an adequate maintenance dose captured most of the trial-like benefit. A follow-up Gasoyan et al. study (Obesity 2025, Dec issue) specifically identified cost and insurance-related barriers as the single most common reason for real-world discontinuation — outranking GI intolerance in their cohort. Efficacy failure per se was a minority reason for stopping.
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.

Practical implication for the semaglutide-versus-tirzepatide choice: the drug-versus-drug difference in SURMOUNT-5 is smaller than the adherence-versus-non-adherence difference in any real-world cohort. The trial-grade outcome is the outcome a patient gets when they reach and stay at the maximum tolerated dose for the full protocol. Matching a patient to one of these two drugs should include an honest discussion of cost, insurance friction, side-effect tolerance, and the realism of chronic exposure — because stopping at month three yields a small fraction of the trial-reported effect for either drug.

Switching Between Them

There is no randomised trial directly evaluating tirzepatide after semaglutide failure, or vice versa. Real-world and consensus-guideline practice fills the gap.

Tirzepatide after semaglutide — The most common switch in practice. Typical triggers: weight-loss plateau on semaglutide 2.4 mg, intolerable GI side effects at maximum dose, or failure to reach an individual's weight-loss target. Community and prescriber practice is often to translate the top semaglutide dose (2.4 mg weekly) to a mid-range tirzepatide start — usually 5 mg or 7.5 mg weekly — rather than beginning at the 2.5 mg initiation step, because the patient has already demonstrated tolerance of GLP-1-class signalling. Some clinicians still prefer to restart at 2.5 mg to allow separate dose-finding on the GIP component. Both approaches appear in real-world practice and neither has randomised data behind it.
Semaglutide after tirzepatide — Less common, but used when access, cost, or a preference for an oral option (Wegovy pill, approved December 2025) drives the switch, or when SELECT-grade cardiovascular outcome evidence becomes the prescribing priority for a patient with established CVD. Dose conversion is generally pragmatic: most patients start at 1.0–1.7 mg semaglutide rather than the 0.25 mg initiation dose, again because class tolerance has been demonstrated.
Washout period — Neither drug requires a formal washout when switching within the class. Because both have half-lives in the multi-day range (semaglutide ~7 days, tirzepatide ~5 days), starting the new agent at the next scheduled weekly injection window is the typical approach. For patients switching specifically because of severe GI intolerance, a 1–2 week break before restarting at a lower dose is a reasonable ergonomic choice rather than a pharmacokinetic requirement.
Expect renewed titration effects — Even with class tolerance, the switch commonly produces a brief return of titration-phase nausea, altered gastric emptying, and early satiety. Plan the switch during a period when this is manageable — not during a heavy travel week or peri-operatively.
Combining the two is not standard practice — The two drugs have overlapping GLP-1 receptor activity and combined use has not been evaluated in any pivotal trial. Some off-label or research settings have explored low-dose combinations but this sits outside any guideline-supported framework and the incremental benefit over maximum-tolerated monotherapy with the more efficacious single agent (tirzepatide) is not established.

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. Compounded semaglutide and tirzepatide enforcement discretion by the FDA ended in 2024–early 2025, so pharmacy-compounded GLP-1s are no longer broadly available through compounding pharmacies except in narrow, individualized clinical-need scenarios.

Channel	Semaglutide	Tirzepatide
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 up	LillyDirect 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
Medicare	Limited — 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; enforcement discretion ended 2025	Historically $250–$500 / mo; enforcement discretion ended 2024–2025

Pricing varies by dose, pharmacy, insurance plan, and jurisdiction. The landscape shifts monthly — always confirm current pricing with the manufacturer program, your pharmacy, and your insurer.

When to Choose Which — Decision Framework

If your priority is...	Lean toward	Why
Maximum weight loss	Tirzepatide	SURMOUNT-5: ~6.5 percentage-point advantage at maximum tolerated dose
Existing cardiovascular disease	Semaglutide	SELECT proved absolute MACE reduction vs placebo in non-diabetic CVD
GI tolerability / prior nausea on GLP-1	Tirzepatide	~2× lower GI-related discontinuation in SURMOUNT-5
Longer real-world safety record	Semaglutide	Approved for T2D since 2017 — 8+ years post-marketing data
Moderate-severe OSA with obesity	Tirzepatide	FDA-approved indication (Dec 2024) based on SURMOUNT-OSA trial
Oral-route preference	Semaglutide	Only class with FDA-approved oral forms (Rybelsus for T2D; Wegovy pill for obesity since Dec 2025)
T2D with established ASCVD	Either — class-level benefit	Both carry CV data in diabetic populations (SUSTAIN-6 for sema; SURPASS-CVOT noninferior to dulaglutide for tirz)
Heart failure with preserved EF + obesity	Semaglutide	STEP-HFpEF trials showed functional improvement; tirzepatide data emerging (SUMMIT 2024)
Cost-conscious self-pay	Tirzepatide (LillyDirect vials)	$299 at lowest dose through manufacturer direct, as of Dec 2025 pricing

In practice, many patients start on semaglutide (longer track record, lower entry dose steps) and switch to tirzepatide if weight loss plateaus or GI tolerability becomes the limiting factor. The opposite transition — starting on tirzepatide and switching to semaglutide — is more often driven by a decision to prioritize the SELECT-grade CV evidence or access.

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. Typical PA criteria include a BMI threshold (≥ 30, or ≥ 27 plus at least one obesity-related comorbidity such as hypertension, dyslipidaemia, or obstructive sleep apnea), documentation of a prior supervised weight-loss attempt, and in some plans step therapy through cheaper agents (phentermine, naltrexone/bupropion, orlistat) first. 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 enforcement discretion during the shortage period ended once Novo Nordisk (semaglutide) and Eli Lilly (tirzepatide) declared their products shortage-resolved. Any remaining compounded supply lives in limited, individually-justified scenarios rather than the broad telehealth channels that were active through 2023 and early 2024. Cost and insurance friction is the single most common reason patients discontinue in real-world data (Gasoyan et al., Obesity 2025), so these pricing and coverage questions have direct efficacy implications, not just affordability implications.

Kalios does not sell compounds. Check the manufacturer programs and your insurer for current pricing in your jurisdiction.

Frequently Asked Questions

Which has better cardiovascular benefit?

As of April 2026, semaglutide has the only placebo-controlled cardiovascular-outcome data. SELECT (NEJM 2023, n = 17,604) proved a 20% relative 3-point MACE reduction in non-diabetic overweight and obese adults with preexisting cardiovascular disease. SURPASS-CVOT (NEJM 2025) showed tirzepatide noninferior to dulaglutide — an active comparator that itself carries CV benefit from the REWIND trial — 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). All-cause mortality was ~16% lower on tirzepatide (HR 0.84), and the expanded 4-point MACE endpoint that adds coronary revascularization was significantly reduced (HR 0.88, 95% CI 0.80–0.96). For a patient where direct cardiovascular-event prevention is the dominant prescribing driver, SELECT is currently the most direct evidence base; for a patient where SURPASS-CVOT's noninferiority-plus-mortality-signal is sufficient, tirzepatide is a reasonable choice.

Is compounded the same as brand-name?

No. Compounded semaglutide and tirzepatide preparations — which proliferated during the 2023–2024 shortage period under FDA enforcement discretion — are not FDA-approved products. API source, purity, salt form, and dosing accuracy all varied across 503A (patient-specific) and 503B (outsourcing-facility) pharmacies, and some compounded products used semaglutide sodium or other salt forms not identical to the branded base. Enforcement discretion ended for both agents across 2024–early 2025 once Novo Nordisk and Eli Lilly declared their products shortage-resolved, so the large-scale telehealth compounded channel that was active through 2024 is no longer broadly available. Narrow, individual clinical-need compounding continues in limited scenarios — not as a standard access route.

What about use for type 2 diabetes?

Both have long-established FDA-approved T2D indications — semaglutide (Ozempic) since 2017, oral semaglutide (Rybelsus) since 2019, and tirzepatide (Mounjaro) since 2022. Both lowered HbA1c and weight in head-to-head T2D trials. SURPASS-2 (NEJM 2021) was the dedicated head-to-head in T2D and showed tirzepatide superior to semaglutide 1 mg on HbA1c reduction across all three tested tirzepatide doses. SUSTAIN-6 is the semaglutide cardiovascular-outcome trial in T2D with established CVD or high CV risk; SURPASS-CVOT is the corresponding tirzepatide T2D CV trial. Both support class-consistent CV benefit in diabetic populations with established atherosclerotic cardiovascular disease.

Which has worse GI side effects?

Prevalence of GI adverse events at maximum tolerated dose is similar between the two in SURMOUNT-5 — nausea ~42% semaglutide vs ~44% tirzepatide, diarrhea ~27% vs ~25%, vomiting ~14% in both arms. The durable difference is in severity leading to discontinuation: 5.6% semaglutide versus 2.7% tirzepatide discontinued for GI adverse events over the 72-week trial — roughly a two-fold gap. Community and prescriber experience aligns: patients who failed semaglutide for tolerability often tolerate tirzepatide. The inverse is less commonly reported, which is part of why tirzepatide-after-semaglutide is by far the more common switch in real-world practice.

Can I switch mid-treatment?

Yes. There is no formal washout required to switch within the GLP-1 / dual GIP-GLP-1 class. Most clinicians translate the top tolerated dose across to a mid-range start on the new drug — rather than beginning at the initiation step — because class tolerance has already been demonstrated. Expect a brief period of renewed GI titration effects even with class tolerance. See the Switching Between Them section above for dose-translation specifics in either direction.

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. SURMOUNT-4 (Aronne et al., JAMA 2024) reproduced this pattern with tirzepatide — the placebo-after-36-week-lead-in arm regained a large fraction of initial loss over 52 weeks — and a post-hoc analysis found ≥ 25% weight regain within 1 year in most withdrawn participants, with reversal of initial cardiometabolic gains proportional to the regain. Real-world trajectories appear more variable than the clean trial curves — some patients retain meaningful weight loss after stopping, especially when behavioural interventions continue (Gasoyan et al.) — but the default expectation is that chronic obesity treatment requires chronic exposure.

Next Steps

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Key References

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.)
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Malhotra A, Grunstein RR, Fietze I, et al.; SURMOUNT-OSA Investigators. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. N Engl J Med. 2024 Oct 3;391(13):1193-1205. PMID: 38912654.
Mamas MA, Bays H, Li R, Upadhyay N, Irani T, Senyucel C, Dunn JP, Liu-Seifert H. Tirzepatide compared with semaglutide and 10-year cardiovascular disease risk reduction in obesity: post-hoc analysis of the SURMOUNT-5 trial. Eur Heart J Open. 2025 Sep 2;5(5):oeaf117. doi: 10.1093/ehjopen/oeaf117. PMID: 40980721.
Rodriguez PJ, Goodwin Cartwright BM, Gratzl S, Brar R, Baker C, Gluckman TJ, Stucky NL. Semaglutide vs Tirzepatide for Weight Loss in Adults With Overweight or Obesity. JAMA Intern Med. 2024 Sep 1;184(9):1056-1064. doi: 10.1001/jamainternmed.2024.2525. PMID: 38976257. (Truveta real-world head-to-head, n = 18,386.)
Gasoyan H, Butsch WS, Schulte R, et al. Changes in Weight and Glycemic Control Following Obesity Treatment With Semaglutide or Tirzepatide by Discontinuation Status. Obesity (Silver Spring). 2025 Sep;33(9):1657-1667. doi: 10.1002/oby.24331. (Cleveland Clinic real-world cohort, n = 7,881.)
Gasoyan H, Butsch WS, Casacchia NJ, et al. Reasons for Discontinuation of Obesity Pharmacotherapy With Semaglutide or Tirzepatide in Clinical Practice. Obesity (Silver Spring). 2025 Dec;33(12):2296-2303. doi: 10.1002/oby.70058. PMID: 41039650. (Cost and insurance barriers identified as leading discontinuation reason.)
Aronne LJ, Sattar N, Horn DB, Bays HE, Wharton S, Lin WY, Ahmad NN, Zhang S, Liao R, Bunck MC, Jouravskaya I, Murphy MA; SURMOUNT-4 Investigators. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial. JAMA. 2024 Jan 2;331(1):38-48. doi: 10.1001/jama.2023.24945. PMID: 38078870.
Wilding JPH, Batterham RL, Davies M, et al.; STEP 1 Study Group. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022 Aug;24(8):1553-1564. doi: 10.1111/dom.14725.

Last updated: April 2026 | Profile authored by Kalios Peptides research team

Semaglutide vs Tirzepatide FDA Approved