Tirzepatide acts on two receptors rather than one, and the obvious question was whether that translates into anything a patient would notice. The SURMOUNT program answered it across six trials: obesity alone, obesity with diabetes, obesity after a lifestyle run-in, what withdrawal does, a direct comparison with semaglutide, and a Chinese population with lower baseline BMI. Around them sit three trials that matter for different reasons — sleep apnea, where it became the first drug of any kind approved for the condition; liver disease; and heart failure. SURPASS-2 is included last because it was a diabetes trial that produced the earliest hint of all of this, years before anyone ran it at obesity doses.
Ranked papers
#1SURMOUNT-1
Jastreboff AM, Aronne LJ, Ahmad NN, et al. · N Engl J Med · 2022
What it measured: Body weight change at 72 weeks
The pivotal trial: 2,539 adults carrying obesity without diabetes, spread across three doses — 5, 10 and 15 mg — or placebo, over 72 weeks. The top dose delivered −20.9% against −3.1%, and about 57% of that arm shed a fifth or more of their starting weight — a figure no non-surgical treatment had produced before. It is the basis of Zepbound's November 2023 approval, and the number every subsequent obesity drug gets measured against.
PMID 35658024 ↗NCT04184622 ↗DOI 10.1056/NEJMoa2206038 ↗
#2SURMOUNT-2
Garvey WT, Frias JP, Jastreboff AM, et al. · Lancet · 2023
What it measured: Body weight change at 72 weeks
938 adults who had both excess weight and type 2 diabetes, the population where these drugs reliably underperform. Tirzepatide managed −13.4% at 10 mg and −15.7% at 15 mg against −3.3%, with A1C down about 2.1 points. Roughly two-thirds of the effect seen without diabetes survives — a better retention than semaglutide manages, and the reason a diabetic patient may still be pointed at the weight-labeled product rather than the glycemic one.
PMID 37385275 ↗NCT04657003 ↗DOI 10.1016/S0140-6736(23)01200-X ↗
#3SURMOUNT-3
Wadden TA, Chao AM, Machineni S, et al. · Nat Med · 2023
What it measured: Weight change over 72 weeks, starting after a diet run-in
This one inverts the usual order. Participants first did 12 weeks of intensive diet and behavioral therapy, and only those who had already lost 5% were randomized. Adding tirzepatide from that starting point produced a further −18.4%, while the placebo group put 2.5% back on — bringing the total from original baseline to around 26%. Lifestyle work does not use up the drug's effect; it stacks with it.
PMID 37840095 ↗NCT04657016 ↗DOI 10.1038/s41591-023-02597-w ↗
#4SURMOUNT-4
Aronne LJ, Sattar N, Horn DB, et al. · JAMA · 2024
What it measured: Weight over the year after everyone had already lost about 21%
The withdrawal trial, and the numbers are stark. 670 people had already lost about 20.9% during a 36-week open-label run-in. Those who continued lost a further 5.5%. Those switched to placebo regained 14.0%. ⛔ Two-thirds of a very large weight loss, back within a year, in people who had done everything right. This is the single clearest piece of evidence that stopping is not a neutral act.
PMID 38078870 ↗NCT04660643 ↗DOI 10.1001/jama.2023.24945 ↗
#5SURMOUNT-5
Aronne LJ, Horn DB, le Roux CW, et al. · N Engl J Med · 2025
What it measured: Weight lost at 72 weeks, head to head against semaglutide
The trial everyone wanted: tirzepatide against semaglutide, head to head, at obesity doses, in 751 adults over 72 weeks. Tirzepatide produced −20.2% against −13.7% — a gap of 6.5 percentage points, or roughly half again as much weight lost. It is the strongest evidence available for choosing between the two, and it is why the ordering on our comparison pages goes the way it does.
PMID 40353578 ↗NCT05822830 ↗DOI 10.1056/NEJMoa2416394 ↗
#6SURMOUNT-CN
Zhao L, Cheng Z, Lu Y, et al. · JAMA · 2024
What it measured: Body weight change at week 52
210 Chinese adults given 10 mg, 15 mg or a placebo over a year, producing −13.6% and −17.5% against a placebo group that gained 2.3%. The point of the trial is the population: baseline BMI runs lower across much of Asia, and there was a genuine open question about whether these drugs would translate. They do, at effect sizes close to SURMOUNT-1's. It supported Lilly's 2024 filing in China.
PMID 38819983 ↗NCT05024032 ↗DOI 10.1001/jama.2024.9217 ↗
#7SURMOUNT-OSA
Malhotra A, Grunstein RR, Fietze I, et al. · N Engl J Med · 2024
What it measured: Breathing interruptions per hour of sleep, after a year
469 adults carrying obesity alongside moderate-to-severe obstructive sleep apnea, run as two trials — one in people using CPAP, one in people who were not. Tirzepatide cut apnea-hypopnea events by 25 to 29 an hour against 5 to 6 on placebo, better than halving the index, with 17 to 20% weight loss alongside. ★ This produced the December 2024 approval that made tirzepatide the first drug of any class licensed to treat sleep apnea, and it opened coverage arguments for people whose BMI alone would not qualify them.
PMID 38912654 ↗NCT05412004 ↗DOI 10.1056/NEJMoa2404881 ↗
#8SYNERGY-NASH
Loomba R, Hartman ML, Lawitz EJ, et al. · N Engl J Med · 2024
What it measured: Liver inflammation gone on biopsy at one year, with scarring no worse
190 patients whose MASH and stage F2 or F3 scarring had been confirmed by biopsy, assigned to 5, 10 or 15 mg against placebo across a year. Between 44% and 62% of the treated arms achieved resolution of the steatohepatitis without fibrosis worsening, against 10% on placebo, with 10 to 15% weight loss. ⚠ This is phase 2, on a biopsy endpoint, and phase 3 is still running — but it puts a second mechanism in play for a disease that had almost nothing five years ago.
PMID 38856224 ↗NCT04166773 ↗DOI 10.1056/NEJMoa2401943 ↗
#9SUMMIT
Packer M, Zile MR, Kramer CM, et al. · N Engl J Med · 2025
What it measured: Cardiac death or worsening heart failure, plus how patients rated their symptoms
731 patients carrying obesity alongside heart failure of the preserved-ejection-fraction type. Tirzepatide cut the combined risk of cardiovascular death or worsening heart failure by 38%, and improved symptom scores by 6.9 points more than placebo, alongside around 14% weight loss. Read alongside STEP-HFpEF for semaglutide, it makes obesity-related heart failure look like something these drugs treat rather than something they incidentally help.
PMID 39555826 ↗NCT04847557 ↗DOI 10.1056/NEJMoa2410027 ↗
#10SURPASS-2
Frías JP, Davies MJ, Rosenstock J, et al. · N Engl J Med · 2021
What it measured: Blood sugar control at 40 weeks — weight was a secondary measure
Included last because it came first. SURPASS-2 was designed to test blood sugar in 1,879 people with type 2 diabetes, and weight was a secondary measure — but over 40 weeks tirzepatide produced 7.6, 9.3 and 11.2 kg of loss at its three doses against 5.7 kg for semaglutide at 1 mg, while also controlling glucose better. It was the first randomized signal that hitting two receptors beats hitting one, years before SURMOUNT-5 confirmed it at the doses people actually take for weight.
PMID 34170647 ↗NCT03987919 ↗DOI 10.1056/NEJMoa2107519 ↗
About this list
We curate ranked, citation-anchored PubMed paper lists for the most-searched questions in obesity medicine. Every citation on this page was checked against PubMed on 2026-08-16. Each paper card links directly to PubMed and to ClinicalTrials.gov where applicable.
Browse our full index of research lists or our long-form research articles.
See also: our tirzepatide overview page.