GLP-1 Trial Deep-Dives: Reading Past the Headline Number
One walkthrough per pivotal GLP-1 trial. Each takes the primary endpoint first, then works through the secondaries one by one, the adverse-event rates, and whichever subgroups were named in advance — with the primary publication and the ClinicalTrials.gov record cited throughout.
STEP-1: The Trial That Set the Semaglutide Benchmark
STEP-1 · Phase 3 · N=1,961
STEP-1 is the reason a weight-loss drug became a household subject. Semaglutide 2.4 mg against placebo in 1,961 people carrying obesity but not diabetes produced −14.9% body weight at 68 weeks, against −2.4% on placebo, and 86.4% of the treated group lost at least 5%. It established the Wegovy dose and the modern benchmark for what a GLP-1 can do. It is also the single most quoted figure in this market, which is why it is worth knowing precisely what was in the syringe and who was in the trial.
SURMOUNT-1: Tirzepatide's 20.9% and What Sits Behind It
SURMOUNT-1 · 3 · N=2,539
SURMOUNT-1 put tirzepatide at 5, 10 and 15 mg weekly against placebo in 2,539 adults who had obesity, or excess weight plus a related complication. The top dose reached -20.9% body weight at 72 weeks against -3.1% on placebo — more than any approved weight drug had achieved in a phase 3 trial, and the evidence behind Zepbound's approval. It also reset what the whole market claims it can deliver, including products carrying no trial evidence whatsoever.
SELECT: When a Weight Drug Became a Cardiac Drug
SELECT · 3 · N=17,604
SELECT enrolled 17,604 adults aged 45 and over with a BMI of at least 27 and existing cardiovascular disease and no diabetes, then followed them a mean 34.2 months on semaglutide 2.4 mg or placebo. Three-point MACE occurred in 6.5% against 8.0% — a 20% relative reduction. It is the largest and most consequential trial in this section, because it moved semaglutide from a drug that changes how people look to a drug shown to prevent heart attacks and strokes.
SURMOUNT-5: The Head-to-Head, Run Properly
SURMOUNT-5 · Phase 3b · N=751
Almost every comparison of tirzepatide and semaglutide is made by setting two separate trials side by side, which is weak evidence however confident it sounds. SURMOUNT-5 did it properly: one protocol, one population, both drugs, 751 adults over 72 weeks. Tirzepatide reached −20.2% against semaglutide's −13.7%, a 6.5-percentage-point gap. It is the single most useful trial in this section for anyone deciding between the two, and it is the one worth citing instead of the cross-trial arithmetic.
SURPASS-2: Tirzepatide Against Semaglutide in Diabetes
SURPASS-2 · Phase 3 · N=1,879
Before SURMOUNT-5 compared these drugs for weight, SURPASS-2 compared them for diabetes. In 1,879 adults on metformin with HbA1c between 7.0% and 10.5%, tirzepatide 15 mg lowered HbA1c by 2.30 percentage points against semaglutide 1 mg's 1.86, and produced roughly twice the weight loss. It is the trial most often cited for the claim that tirzepatide is simply stronger — a claim it supports, at these doses, in this population.
STEP-4: What Happens When You Stop
STEP-4 · Phase 3a · N=803
STEP-4 is the trial that ended the idea of a GLP-1 course. Every participant reached semaglutide 2.4 mg during a 20-week run-in, then was randomized two-to-one to continue or move to placebo for 48 more weeks. Those who continued lost a further 7.9% of body weight. Those who switched regained 6.9%. Same people, same starting point, one variable. It is the shortest route to understanding why this is chronic therapy, and it is the trial to read before signing a twelve-month prepay or planning an exit.
SURMOUNT-OSA: Tirzepatide for Sleep Apnea
SURMOUNT-OSA · Phase 3 · N=469
SURMOUNT-OSA tested tirzepatide in 469 people carrying obesity alongside moderate-to-severe obstructive sleep apnea, split into two cohorts — those using positive airway pressure and those not. The apnea-hypopnea index fell 25.3 events an hour without PAP and 29.3 with it, against roughly 5 on placebo. It produced a second FDA indication for Zepbound and turned a weight-management drug into a treatment for a specific, diagnosable condition.
SYNERGY-NASH: Tirzepatide and Liver Disease
SYNERGY-NASH · Phase 2 · N=190
SYNERGY-NASH is the most methodologically demanding trial in this section, because its endpoint required a liver biopsy at the start and another at 52 weeks. In 190 adults with biopsy-proven MASH and stage F2 or F3 fibrosis, 62% on tirzepatide 15 mg achieved MASH resolution without worsening fibrosis, against 10% on placebo. It positions this class as a systemic therapy for liver disease rather than only for weight.
SUSTAIN-6: The First Semaglutide Outcomes Signal
SUSTAIN-6 · Phase 3 · N=3,297
SUSTAIN-6 was designed as a safety trial and returned a benefit. Across a median 2.1 years, in 3,297 people whose diabetes came with high cardiac risk, the three-part endpoint hit 6.6% of the semaglutide group and 8.9% of the placebo group. It established the cardiovascular signal that SELECT would later confirm in a population without diabetes, and it is the trial behind Ozempic's cardiovascular labeling.
LEADER: The Trial That Started the Class Story
LEADER · Phase 3b/4 · N=9,340
LEADER was the first trial to show a GLP-1 reducing cardiovascular events, and everything the class now claims about the heart traces back to it. In 9,340 people whose type 2 diabetes came with established heart disease or high risk, tracked for a median 3.8 years, MACE occurred in 13.0% on liraglutide against 14.9% on placebo. The drug it tested is now commercially overtaken, but the finding shaped how every GLP-1 after it was developed and judged.
FLOW: Semaglutide and the Kidneys
FLOW · Phase 3b · N=3,533
FLOW asked whether semaglutide slows kidney disease, in 3,533 people whose type 2 diabetes had damaged their kidneys, tracked for a median 3.4 years. The composite outcome — kidney failure, sustained eGFR decline, or renal or cardiovascular death — occurred in 18.7% against 23.2% on placebo, a 24% relative reduction. The independent monitoring committee stopped it early because the benefit was clear enough that continuing the placebo arm was no longer justified.
SURMOUNT-2: Tirzepatide When You Also Have Diabetes
SURMOUNT-2 · 3 · N=938
SURMOUNT-2 ran tirzepatide in the population SURMOUNT-1 excluded: adults with type 2 diabetes as well as obesity. At 15 mg the result was −14.7% body weight at 72 weeks against −3.2% on placebo. That is a substantial effect and it is six percentage points below what the same drug produced in people without diabetes, which is the single most useful comparison anyone with diabetes can make when reading marketing built on SURMOUNT-1.
STEP-2: Semaglutide With Type 2 Diabetes
STEP-2 · Phase 3 · N=1,210
STEP-2 is to STEP-1 what SURMOUNT-2 is to SURMOUNT-1: the same drug and design, in people who also have type 2 diabetes. Semaglutide 2.4 mg produced −9.6% body weight at 68 weeks against −3.4% on placebo, alongside a 1.6-point HbA1c reduction. Against STEP-1's −14.9%, the five-point gap is the price of the diabetes, and it is the number a reader with diabetes should be working from.
STEP-3: Adding Intensive Behavioral Therapy
STEP-3 · Phase 3a · N=611
STEP-3 paired semaglutide with intensive behavioral therapy: 30 counseling visits over 68 weeks plus an initial low-calorie diet. The drug arm reached −16.0%, the highest in the STEP program. The number worth pausing on is the other one — placebo plus the same intensive therapy reached −5.7%, roughly double what placebo achieved in STEP-1. Both arms did better with the support, which is the honest reading of what behavioral therapy contributes.
REWIND: Dulaglutide in a Primary-Prevention Population
REWIND · Phase 3 · N=9,901
REWIND followed 9,901 people living with type 2 diabetes for a median 5.4 years, the longest of any GLP-1 outcomes trial, and reported MACE in 12.0% against 13.4% on placebo. The relative reduction, 12%, is the smallest of the positive trials in this class — and the population is the reason it matters. Only 31% had established cardiovascular disease, making this largely a primary-prevention trial, where showing benefit is considerably harder.
AWARD-7: Dulaglutide With Impaired Kidney Function
AWARD-7 · Phase 3 · N=577
AWARD-7 tested dulaglutide against titrated insulin glargine in 577 people whose type 2 diabetes came with moderate-to-severe kidney disease — a population usually excluded from diabetes trials. HbA1c fell 1.19 points on dulaglutide 1.5 mg against 1.13 on insulin, with less weight gain and fewer hypoglycemic episodes. It is a comparative-effectiveness trial rather than an outcomes trial, and it addresses a group that has few good options.
SURMOUNT-3: Tirzepatide After a Lifestyle Run-In
SURMOUNT-3 · 3 · N=579
SURMOUNT-3 answered a question the other trials skip: what does the drug add for someone who has already succeeded with lifestyle change? All 579 participants completed a 12-week intensive lifestyle lead-in first. Those randomized to tirzepatide then lost a further 18.4%; those on placebo regained 2.5%. The design isolates the drug's contribution on top of behavioral success rather than instead of it.
SUSTAIN-7: Semaglutide Against Dulaglutide
SUSTAIN-7 · Phase 3b · N=1,201
SUSTAIN-7 compared semaglutide against dulaglutide head-to-head at matched dose levels in 1,201 people living with type 2 diabetes across 40 weeks. Semaglutide 0.5 mg lowered HbA1c 1.5 points against dulaglutide 0.75 mg's 1.1, with the same direction at the higher pairing, and produced more weight loss at both. It is one of the few direct comparisons between two weekly GLP-1s and it settled which is the more potent.
AMPLITUDE-O: A Positive Trial for a Drug Nobody Can Buy
AMPLITUDE-O · Phase 3 · N=4,076
AMPLITUDE-O tested efpeglenatide, a weekly GLP-1, in 4,076 people whose type 2 diabetes carried high cardiac risk, and reported the endpoint in 7.0% against 9.2% on placebo — a 27% relative reduction, among the larger effects in the class. The drug was then not brought to the US market. It is a useful reminder that trial success and availability are separate questions decided by different people for different reasons.
SURMOUNT-CN: Tirzepatide in Chinese Adults
SURMOUNT-CN · Phase 3 · N=210
SURMOUNT-CN ran tirzepatide in 210 Chinese adults with obesity over 52 weeks, reporting −17.5% at 15 mg against −2.3% on placebo. Its purpose is regulatory and scientific rather than commercial: obesity trials have been overwhelmingly conducted in North American and European populations, and whether results transfer is a real question rather than a formality, given differences in baseline BMI, body composition and diabetes prevalence.
HARMONY OUTCOMES: A Win for a Withdrawn Drug
HARMONY OUTCOMES · Phase 3 in substance, logged on the registry as Phase 4 because it ran after approval as a cardiovascular outcomes study · N=9,463
HARMONY OUTCOMES followed 9,463 people whose type 2 diabetes came with established heart disease, tracked for a median 1.6 years, reporting MACE in 7% against 9% on placebo — a 22% relative reduction, among the strongest in the class. GSK had already withdrawn albiglutide from global markets the year before the results published, for commercial reasons rather than safety. The evidence outlived the product.
ELIXA: The First One, and It Was Neutral
ELIXA · Phase 3 · N=6,068
This was the first cardiovascular outcomes trial in the class to finish under the safety rules the FDA imposed after 2008, testing lixisenatide in 6,068 people with type 2 diabetes in the months after an acute coronary event. The four-point composite occurred in 13.4% against 13.2% on placebo — non-inferior, not superior. It established the safety the guidance required and found no benefit, which is the correct outcome to remember when reading class-wide claims.
SUMMIT: Tirzepatide in Heart Failure
SUMMIT · Phase 3 · N=731
SUMMIT tested tirzepatide in 731 people carrying obesity alongside the stiff-heart form of heart failure, over a minimum 52 weeks. Cardiac death or heart failure getting worse happened to 9.9% against 15.3% on placebo. It is the tirzepatide counterpart to STEP-HFpEF and, unlike that trial, it measured hard events rather than symptom scores.
STEP-HFpEF: Measuring How People Actually Feel
STEP-HFpEF · Phase 3 · N=529
STEP-HFpEF tested semaglutide 2.4 mg in 529 people carrying obesity alongside the stiff-heart form of heart failure, using the Kansas City Cardiomyopathy Questionnaire as its primary endpoint. Scores improved 16.6 points against 8.7 on placebo. Five points is considered clinically meaningful, so the difference between arms is itself well past that bar — and the endpoint measures breathlessness and physical limitation rather than a laboratory value.
EXSCEL: The Large Neutral Result
EXSCEL · Phase 3/4 · N=14,752
EXSCEL is the largest trial in this section and returned nothing on its primary endpoint. Once-weekly exenatide in 14,752 people living with type 2 diabetes produced the endpoint in 11.4% against 12.2% on placebo over a median 3.2 years — a difference that did not reach significance. It sits alongside ELIXA as the counterexample to any claim that cardiovascular benefit is automatic across this class.
SCALE Teens: Liraglutide in Adolescents
SCALE Teens · Phase 3 · N=251
SCALE Teens tested liraglutide 3.0 mg in 251 adolescents aged 12 to 17 with obesity, over 56 weeks. BMI standard-deviation score — the measure used in growing bodies, where raw BMI moves with development — fell 0.23 against essentially no change on placebo. It supported the 2020 extension of Saxenda's label down to age 12 and was among the first trials to take adolescent obesity pharmacotherapy seriously.
PIONEER 6: Cardiovascular Safety for the Tablet
PIONEER 6 · Phase 3a · N=3,183
PIONEER 6 asked whether swallowing semaglutide instead of injecting it costs anything cardiovascularly. In 3,183 people whose type 2 diabetes carried high cardiac risk, over a median 15.9 months, MACE occurred in 3.8% against 4.8% on placebo — non-inferior, with a point estimate favoring the drug in a trial not powered to show superiority.
SCALE Maintenance: Holding On to a Loss
SCALE Maintenance · Phase 3 · N=422
SCALE Maintenance tested whether a GLP-1 helps people keep weight they have already lost. All 422 participants completed a low-calorie diet run-in first, then were randomized. Over 56 weeks the liraglutide arm lost a further 6.2% while the placebo arm lost 0.2%. It is an early version of the question STEP-4 later answered more sharply, and it points the same way.
STEP 7: Semaglutide in East Asian Populations
STEP 7 · Phase 3a · N=375
STEP 7 ran semaglutide 2.4 mg over 44 weeks in 375 adults, reporting −12.1% mean body weight against −3.6% on placebo. Its purpose is the same as SURMOUNT-CN's: the pivotal obesity trials enrolled overwhelmingly Western populations, and whether the effect transfers is a question that deserves measurement rather than assumption.
SCALE Diabetes: Liraglutide With Type 2 Diabetes
SCALE Diabetes · Phase 3 · N=846
SCALE Diabetes tested liraglutide 3.0 mg and 1.8 mg in 846 adults with obesity and type 2 diabetes over 56 weeks. The 3.0 mg arm reached −6.0% body weight against −2.0% on placebo, with 1.8 mg landing in between at −4.7%. It established the indication Saxenda still holds in this population, and it is a clear illustration of the dose-response relationship that runs through this whole class.