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Obesity and weight loss

Weight-loss drugs compared: which one works best, according to the trials

The comparison the evidence actually supports — and the questions that matter more than a ranking of kilos. Educational content, no brand recommended.

Dr. Diegomaier Nunes NeriBy Dr. Diegomaier Nunes Neri, physician · CRM-SC 32925 | CRM-BA 39586 (Brazil) · reviewed on · 12 min read
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In short
  • By average loss: tirzepatide (14.8%) > semaglutide (12.0%) > liraglutide (6.8%) ≈ naltrexone + bupropion (4.8%) ≈ sibutramine > orlistat (2.1%), placebo-subtracted.
  • Only three head-to-head trials exist; everything else is separate trials placed side by side.
  • Weight is not the only outcome: only semaglutide 2.4 mg has a trial showing fewer heart attacks, strokes and cardiovascular deaths.
  • The choice depends on the kind of hunger, contraindications, route and what you can sustain — not on the ranking.
  • For all of them, stopping returns part of the weight. Obesity is a chronic disease.

First of all: this text compares scientific evidence about substances, not commercial products. Brand names appear once each, only so you can recognise them on a prescription. I recommend none of them, I receive nothing from any manufacturer, and no medicine here should be started, switched or stopped on the basis of something read online. All of them require a prescription, and approved indications and brand names differ by country.

Short answer: by average weight loss in trials, the order is tirzepatide > semaglutide > liraglutide ≈ naltrexone + bupropion ≈ sibutramine > orlistat. Guidelines separate high-potency drugs (more than 10% placebo-subtracted loss) from low-to-moderate (4% to 9.9%) and very low (under 4%) (ABESO, ABESO 2026).

But "which one takes off the most weight" is the wrong question for the person who will take it. The right question is which one makes sense for you — and that depends on your contraindications, the kind of hunger you have, tablet or injection, what you can sustain for years, and what has actually been proven about the heart. That is what I set out below.

The table that sums it up

Weight loss with placebo already subtracted, at 52 weeks, from the meta-analyses pooled in current guidelines (ABESO, ABESO 2026; McGowan et al., Nat Med 2025). It is the fairest comparison: it strips out the effect of simply being in a trial under close follow-up.

SubstanceLoss beyond placeboPotency bandRoute
Tirzepatide14.8%HighWeekly injection
Semaglutide 2.4 mg12.0%HighWeekly injection
Liraglutide 3.0 mg6.8%Low to moderateDaily injection
Naltrexone + bupropion4.8%Low to moderateTablet, up to 4/day
Sibutramine4.2 kgLow to moderateCapsule, once daily
Orlistat2.1%Very lowCapsule, 3×/day

swipe the table sideways →

For scale, in the individual trials: tirzepatide 15 mg produced −20.9% at 72 weeks (Jastreboff et al., N Engl J Med 2022 — SURMOUNT-1); semaglutide 2.4 mg −14.9% at 68 weeks (Wilding et al., N Engl J Med 2021 — STEP 1); liraglutide 3.0 mg −8.0% at 56 weeks (Pi-Sunyer et al., N Engl J Med 2015 — SCALE); naltrexone + bupropion −6.1% at 56 weeks (Greenway et al., Lancet 2010 — COR-I); orlistat −5.8 kg over 4 years (Torgerson et al., Diabetes Care 2004 — XENDOS).

The only head-to-head comparisons that exist

Almost everything said about this is indirect comparison — different trials, different populations. Head to head, there are only three:

Head-to-headResultTrial
Tirzepatide vs semaglutide 2.4 mg−20.2% vs −13.7%SURMOUNT-5, 72 weeks, open-label (Aronne et al., N Engl J Med 2025 — SURMOUNT-5)
Semaglutide 2.4 mg vs liraglutide 3.0 mg−15.8% vs −6.4%STEP 8, 68 weeks, open-label (Rubino et al., JAMA 2022 — STEP 8)
Semaglutide 7.2 mg vs 2.4 mg−18.7% vs −15.6%STEP UP, 72 weeks (Wharton et al., Lancet Diabetes Endocrinol 2025 — STEP UP)

swipe the table sideways →

Note that no trial has compared a tablet with an injection head to head. When someone says a given pen "works twice as well as the tablet", they are adding up results from separate trials — a reasonable estimate, not a measurement.

Weight loss is not the only outcome

Losing weight is a means, not the end. What changes a life is what happens to the heart, to diabetes and to longevity. And here the picture differs from the table above.

How the choice is actually made

1. What kind of hunger do you have?

Some people feel physical hunger — an empty stomach, large meal volumes, satiety that never arrives. Others feel wanting — food "calls" even without hunger, the late-afternoon sweet, grazing out of anxiety. Different brain circuits. GLP-1 agonists act mainly on physical satiety; naltrexone + bupropion acts mainly on craving and reward. A study that chose the drug by eating phenotype achieved 15.9% loss in a year against 9.0% with the usual approach (Acosta et al., Obesity 2021).

2. What stops you from using the most potent one?

Guidelines say to use high potency whenever possible (ABESO, ABESO 2026). "Whenever possible" falls apart in the face of unaffordable cost, supply shortages, fear of or inability to inject, GLP-1 intolerance, a history of pancreatitis, or medullary thyroid cancer in the family. These are legitimate and common reasons — and then the less potent option becomes the better real option, because the most potent medicine is no use if the person cannot take it.

3. Does a contraindication already rule options out?

Epilepsy, bipolar disorder, opioid use and uncontrolled hypertension rule out naltrexone + bupropion. Medullary thyroid cancer, MEN 2 and prior pancreatitis rule out GLP-1 agonists. Established cardiovascular disease rules out sibutramine. This question alone usually halves the list.

4. Can you sustain it?

Obesity is a chronic disease. In the withdrawal trials much of the weight returned: in STEP 4, people who stopped semaglutide regained while those who continued kept losing (Rubino et al., JAMA 2021 — STEP 4); SURMOUNT-4 showed the same for tirzepatide (Aronne et al., JAMA 2024 — SURMOUNT-4). Choosing a treatment you will not be able to maintain is choosing regain with a date on it.

5. Is follow-up part of the plan?

Probably the most underrated part. In COR-BMOD the same drug that gave 6% gave 9.3% when paired with 28 behaviour-modification sessions over the year (Wadden et al., Obesity 2011 — COR-BMOD). Half the result was not in the box.

Can two drugs be combined?

Guidelines allow it when the response has been insufficient, within clear limits (ABESO, ABESO 2026): combining GLP-1 agonists with one another is not recommended; combining sibutramine with naltrexone + bupropion is not recommended; pairing a GLP-1 agonist with naltrexone + bupropion is among the acceptable options on observational data, but the guideline itself records that those data did not hold up on reanalysis. Combining two obesity drugs is generally off-label and belongs with clinicians experienced in treating obesity.

What no text can tell you

No table decides your case. The differences above are averages of thousands of people: within every trial, some lost 25% and some lost nothing on the same drug. Your result depends on genetics, comorbidities, the dose you tolerate, what you can maintain and the follow-up you get. That is exactly why these medicines require a prescription and an individual assessment — and why I recommend none of them here.

What this text can do is give you vocabulary for the consultation.

Frequently asked questions

Which weight-loss drug works best?

By average weight loss in trials, tirzepatide, followed by semaglutide. Placebo-subtracted, tirzepatide sits around 14.8% and semaglutide around 12.0%, against 6.8% for liraglutide, 4.8% for naltrexone + bupropion and 2.1% for orlistat. But working best on average is not the same as being right for one person.

Are there head-to-head comparisons?

Few. Tirzepatide versus semaglutide 2.4 mg (SURMOUNT-5: −20.2% vs −13.7%), semaglutide 2.4 mg versus liraglutide 3.0 mg (STEP 8: −15.8% vs −6.4%) and semaglutide 7.2 mg versus 2.4 mg (STEP UP). No trial has compared a tablet with an injection head to head.

Is the tablet worse than the injection?

For average weight loss, yes: the GLP-1 injectables produce more. But the tablet has real advantages — no needle, lower cost, and it acts on craving and emotional eating, which is many people's pattern. The treatment that works is the one a person can keep up.

Which is safest for the heart?

Semaglutide 2.4 mg is the only one with a trial measuring cardiovascular outcomes that showed fewer heart attacks, strokes and cardiovascular deaths in people with cardiovascular disease and without diabetes. For naltrexone + bupropion the cardiovascular trial was stopped early and the question remains open. For sibutramine, a trial showed more events in people who already had heart disease.

Will the weight come back if I stop?

Part of it does, in most people — that is what the withdrawal trials of both semaglutide and tirzepatide showed. It is not a failure of character or of the drug: it is the physiology of the disease.

Can I combine two of them?

Guidelines allow it for insufficient response, but do not recommend combining GLP-1 agonists with one another, nor sibutramine with naltrexone + bupropion. Combining two obesity drugs is generally off-label and requires clinical experience. Never combine on your own.

Do they all need a prescription?

Yes. Every medicine mentioned here is prescription-only, and several are under special control. Any site or account offering them without a prescription is operating illegally.

References

  1. ABESO. DIRETRIZ BRASILEIRA DE TRATAMENTO FARMACOLÓGICO DA OBESIDADE. ABESO. 2026. doi:10.47626/2026-abeso-0001
  2. McGowan B, Ciudin A, Baker JL, et al. A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults. Nat Med. 2025;31(10):3317-3329. doi:10.1038/s41591-025-03978-z
  3. Khera R, Murad MH, Chandar AK, et al. Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events. JAMA. 2016;315(22):2424. doi:10.1001/jama.2016.7602
  4. Shi Q, Wang Y, Hao Q, et al. Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials. Lancet. 2024;403(10434):e21-e31. doi:10.1016/s0140-6736(24)00351-9
  5. Damen JA, Idema DL, Vernooij RW, et al. Benefits and Harms of Pharmacologic Treatments in Adults With Overweight or Obesity: A Living Systematic Review and Network Meta-analysis for the American College of Physicians. Ann Intern Med. 2026;179(8):1140-1155. doi:10.7326/annals-24-03764
  6. Wilding JP, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity [STEP 1]. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/nejmoa2032183
  7. Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes [STEP 8]. JAMA. 2022;327(2):138. doi:10.1001/jama.2021.23619
  8. Wharton S, Freitas P, Hjelmesæth J, et al. Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial [STEP UP]. Lancet Diabetes Endocrinol. 2025;13(11):949-963. doi:10.1016/s2213-8587(25)00226-8
  9. Rubino D, Abrahamsson N, Davies M, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity [STEP 4]. JAMA. 2021;325(14):1414. doi:10.1001/jama.2021.3224
  10. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes [SELECT]. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/nejmoa2307563
  11. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity [SURMOUNT-1]. N Engl J Med. 2022;387(3):205-216. doi:10.1056/nejmoa2206038
  12. Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity [SURMOUNT-5]. N Engl J Med. 2025;393(1):26-36. doi:10.1056/nejmoa2416394
  13. Aronne LJ, Sattar N, Horn DB, et al. Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity [SURMOUNT-4]. JAMA. 2024;331(1):38. doi:10.1001/jama.2023.24945
  14. Pi-Sunyer X, Astrup A, Fujioka K, et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management [SCALE]. N Engl J Med. 2015;373(1):11-22. doi:10.1056/nejmoa1411892
  15. Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial [COR-I]. Lancet. 2010;376(9741):595-605. doi:10.1016/s0140-6736(10)60888-4
  16. Wadden TA, Foreyt JP, Foster GD, et al. Weight Loss With Naltrexone SR/Bupropion SR Combination Therapy as an Adjunct to Behavior Modification: The COR‐BMOD Trial [COR-BMOD]. Obesity. 2011;19(1):110-120. doi:10.1038/oby.2010.147
  17. Nissen SE, Wolski KE, Prcela L, et al. Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors [LIGHT]. JAMA. 2016;315(10):990. doi:10.1001/jama.2016.1558
  18. James WPT, Caterson ID, Coutinho W, et al. Effect of Sibutramine on Cardiovascular Outcomes in Overweight and Obese Subjects [SCOUT]. N Engl J Med. 2010;363(10):905-917. doi:10.1056/nejmoa1003114
  19. Torgerson JS, Hauptman J, Boldrin MN, et al. XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study [XENDOS]. Diabetes Care. 2004;27(1):155-161. doi:10.2337/diacare.27.1.155
  20. Acosta A, Camilleri M, Abu Dayyeh B, et al. Selection of Antiobesity Medications Based on Phenotypes Enhances Weight Loss: A Pragmatic Trial in an Obesity Clinic. Obesity. 2021;29(4):662-671. doi:10.1002/oby.23120
  21. ANVISA. Bula do profissional de saúde — naltrexona 8 mg + bupropiona 90 mg. Texto aprovado em 19/06/2026. Bulário Eletrônico
  22. ANVISA. Carta aos profissionais de saúde — naltrexona/bupropiona: risco cardiovascular a longo prazo e avaliação anual. 19 de maio de 2026. gov.br/anvisa
  23. ANVISA. Tirzepatida — inclusão de nova indicação terapêutica (controle crônico de peso). RESOLUÇÃO-RE nº 2.144, de 06/06/2025, DOU de 09/06/2025. in.gov.br
  24. ANVISA. Semaglutida 2,4 mg — registro de produto novo. RESOLUÇÃO-RE nº 4.310, de 29/12/2022, DOU de 02/01/2023. in.gov.br

Read also

Important: This content is strictly educational and must never be used for self-diagnosis, self-medication, treatment selection or as a substitute for a consultation. Responsibility for the use of this information lies entirely with the reader.

About the brand names mentioned. This text compares published scientific evidence about active ingredients, not commercial products. Brand names appear once, in brackets, only so readers can recognise which substance is meant on a prescription or at the pharmacy. There is no recommendation, endorsement, commercial comparison or encouragement to use any brand. No product is presented as superior for an individual reader: the differences described are population averages from clinical trials and do not predict any one person's result. Approved indications, brand names and availability differ by country.

Conflict of interest statement: I declare that I have no link, sponsorship, contract, shareholding or payment of any kind from any of the pharmaceutical companies mentioned, directly or indirectly. This content is unsponsored and published free of charge.

All medicines mentioned are prescription-only and several are subject to special control. Choosing an obesity treatment depends on individual medical assessment. No obesity medicine should be started, switched or stopped on the basis of this or any other text on the internet.

Written and reviewed by a physician, with primary references and verifiable DOIs. Every person is unique and must be assessed individually.

Dr. Diegomaier Nunes Neri
Dr. Diegomaier Nunes Neri

Physician (CRM-SC 32925 | CRM-BA 39586, Brazil). Sees patients by video consultation in Brazil and abroad. This content is educational, reviewed against the cited references, and does not replace a consultation.

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Reviewed on November 6, 2026 by Dr. Diegomaier Nunes Neri — CRM-SC 32925 | CRM-BA 39586 (Brazil).