GLP-1 Trial Deep-Dives: Every Secondary Endpoint Decoded
Structured walkthroughs of pivotal GLP-1 trials. Each deep-dive decodes the primary endpoint, every secondary endpoint, AE rates, and pre-specified subgroup analyses with citations to the primary publication + ClinicalTrials.gov registry.
STEP-1 trial deep-dive: semaglutide 2.4 mg for obesity (Wilding 2021 NEJM)
STEP-1 · Phase 3 · N=1,961
STEP-1 is the pivotal NEJM trial that established once-weekly semaglutide 2.4 mg as a category-defining obesity drug. This deep-dive walks through every reported endpoint — body weight, waist, blood pressure, hs-CRP, HbA1c, IWQOL-Lite-CT, SF-36 — with the actual numbers from the Wilding 2021 publication and the ClinicalTrials.gov results posting, plus adverse-event incidence and FAQs about run-in, dose tolerance, and durability after treatment ends.
Last verified 2026-05-27
SURMOUNT-1 deep dive: tirzepatide 5/10/15 mg vs placebo at 72 weeks
SURMOUNT-1 · 3 · N=2,539
SURMOUNT-1 randomized 2,539 adults with obesity (without diabetes) to once-weekly tirzepatide 5 mg, 10 mg, 15 mg, or placebo for 72 weeks. The 15-mg arm lost a mean 20.9% of body weight on the treatment-regimen estimand (NEJM publication) vs 3.1% with placebo; 91% achieved at least 5% loss and 57% achieved at least 20% loss. Every prespecified cardiometabolic measure — waist, systolic blood pressure, fasting insulin, triglycerides, HbA1c — improved. GI adverse events were dose-dependent and discontinuations for AEs ran 4.3-7.1% on tirzepatide vs 2.6% on placebo.
Last verified 2026-05-27
SELECT trial deep-dive: semaglutide cuts MACE 20% in obesity without diabetes
SELECT · 3 · N=17,604
SELECT (Lincoff 2023, NEJM, PMID 37952131) was the first cardiovascular-outcomes trial of a GLP-1 receptor agonist run in adults with obesity but no diabetes. Across 17,604 participants followed a mean 39.8 months, weekly semaglutide 2.4 mg reduced the primary three-point MACE composite by 20% versus placebo. The result moved semaglutide from a weight-loss drug into the cardioprotection conversation and underpinned Wegovy's March 2024 FDA label expansion to reduce MACE risk in adults with obesity and established cardiovascular disease.
Last verified 2026-05-27
SURMOUNT-5 deep dive: tirzepatide vs semaglutide head-to-head at 72 weeks
SURMOUNT-5 · Phase 3b · N=751
SURMOUNT-5 is the first and only randomized head-to-head trial comparing tirzepatide (Zepbound) with semaglutide (Wegovy) in adults with obesity but without type 2 diabetes. Eli Lilly randomized 751 participants 1:1 to the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) for 72 weeks. The least-squares mean weight loss was −20.2% with tirzepatide vs −13.7% with semaglutide (P<0.001), a 6.5-percentage-point advantage. Tirzepatide also produced a larger waist-circumference reduction (−18.4 cm vs −13.0 cm) and roughly double the proportion of participants reaching ≥25% weight loss (36.5% vs 18.6%). Gastrointestinal adverse-event profiles were broadly similar, with vomiting and GERD numerically less common on tirzepatide and injection-site reactions more common.
Last verified 2026-05-27
SURPASS-2 deep-dive: tirzepatide vs semaglutide 1 mg head-to-head in T2D (Frias 2021)
SURPASS-2 · Phase 3 · N=1,879
SURPASS-2 (Frias 2021 NEJM, PMID 34170647) is the first registrational head-to-head comparison of two incretin agonists. 1,879 adults with type 2 diabetes inadequately controlled on metformin were randomized to once-weekly subcutaneous tirzepatide 5 mg, 10 mg, 15 mg, or semaglutide 1 mg for 40 weeks. Tirzepatide produced larger reductions in HbA1c (−2.01 to −2.30 percentage points vs −1.86 with semaglutide) and in body weight (−7.6 to −11.2 kg vs −5.7 kg) across every dose, with a similar GI-event profile and low hypoglycemia in both groups. The trial supplied the regulatory case that dual GIP/GLP-1 agonism delivers more glycemic and weight effect per dose than the leading GLP-1 monotherapy at its highest then-approved T2D dose.
Last verified 2026-05-27
STEP-4 deep-dive: what happens when you stop semaglutide (Rubino 2021 JAMA)
STEP-4 · Phase 3a · N=803
STEP-4 is the canonical "if I stop, will the weight come back" trial. After a 20-week open-label run-in on semaglutide 2.4 mg during which participants lost a mean 10.6% of body weight, 803 responders were randomized 2:1 to either continue weekly semaglutide for 48 more weeks or switch to placebo. Those who continued lost another 7.9% on top of run-in losses. Those switched to placebo regained 6.9% over the same 48 weeks — a 14.8 percentage-point swing. Waist circumference, systolic blood pressure, and SF-36 physical-functioning scores all moved in the same direction: maintained on drug, partially reversed off it. STEP-4 is the trial that turned obesity drugs into chronic-disease therapy in the regulatory and clinical conversation.
Last verified 2026-05-27
SURMOUNT-OSA deep dive: tirzepatide for obstructive sleep apnea (Malhotra 2024 NEJM)
SURMOUNT-OSA · Phase 3 · N=469
SURMOUNT-OSA is the pair of phase-3 trials that drove the December 2024 FDA approval of Zepbound (tirzepatide) for moderate-to-severe obstructive sleep apnea in adults with obesity — the first drug ever approved for the condition. Eli Lilly ran two parallel master-protocol cohorts and reported them as one paper (Malhotra 2024 NEJM, PMID 38912654): SURMOUNT-OSA-1 (n=234) randomized adults not using positive airway pressure (PAP) therapy, and SURMOUNT-OSA-2 (n=235) randomized adults already established on PAP. After 52 weeks of weekly tirzepatide at maximum tolerated dose (10 or 15 mg), the apnea-hypopnea index dropped by 25.3 events/hour in cohort 1 (placebo-subtracted −20.0) and 29.3 events/hour in cohort 2 (placebo-subtracted −23.8). Body weight fell about 18-20%, hsCRP dropped roughly 35-40%, and systolic blood pressure fell 7-9 mmHg.
Last verified 2026-05-28
SYNERGY-NASH deep-dive: tirzepatide for MASH with fibrosis (Loomba 2024 NEJM)
SYNERGY-NASH · Phase 2 · N=190
SYNERGY-NASH is the phase 2 biopsy-driven trial that put tirzepatide on the MASH map. Loomba and colleagues randomized 190 adults with biopsy-proven metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) and stage F2 or F3 fibrosis to once-weekly subcutaneous tirzepatide at 5 mg, 10 mg, or 15 mg or matching placebo for 52 weeks, with paired liver biopsies at baseline and week 52. The primary histologic endpoint — MASH resolution without worsening of fibrosis — was met by 10% on placebo versus 44%, 56%, and 62% on tirzepatide 5, 10, and 15 mg respectively. Fibrosis improvement of at least one stage without worsening of MASH also separated from placebo (30% vs 51-55%). The trial provided the proof-of-concept that supported Eli Lilly's phase 3 program in MASH.
Last verified 2026-05-28
SUSTAIN-6 deep-dive: semaglutide MACE outcomes in T2D (Marso 2016 NEJM)
SUSTAIN-6 · Phase 3 · N=3,297
SUSTAIN-6 (Marso 2016, NEJM, PMID 27633186) is the cardiovascular-outcomes trial that earned semaglutide its FDA cardioprotection labeling for Ozempic. Across 3,297 adults with type 2 diabetes at high cardiovascular risk, weekly subcutaneous semaglutide (pooled 0.5 mg and 1.0 mg) reduced the three-point MACE composite by 26% versus placebo over a median 104 weeks. The MACE win was driven primarily by a 39% reduction in nonfatal stroke and a 26% directional reduction in nonfatal myocardial infarction; cardiovascular death and all-cause mortality were unchanged. A 22% reduction in new or worsening nephropathy stood alongside a notable safety signal: diabetic retinopathy complications were 76% more frequent on semaglutide, the trade-off that has shaped every semaglutide CVOT discussion since.
Last verified 2026-05-28
LEADER trial deep-dive: liraglutide cuts MACE 13% in type 2 diabetes (Marso 2016)
LEADER · Phase 3b/4 · N=9,340
LEADER (Marso 2016, NEJM, PMID 27295427) was the cardiovascular-outcomes trial that proved a GLP-1 receptor agonist could lower hard cardiovascular events. Across 9,340 adults with type 2 diabetes and elevated cardiovascular risk followed a median 3.8 years, daily subcutaneous liraglutide 1.8 mg reduced the three-point MACE composite by 13% versus placebo. LEADER's NEJM publication on July 28, 2016 — months before SUSTAIN-6 reported for semaglutide — was the first positive GLP-1 CVOT and established the cardioprotective paradigm that the entire class now inherits.
Last verified 2026-05-28
FLOW trial deep-dive: semaglutide cuts kidney-disease progression 24% in T2D (Perkovic 2024)
FLOW · Phase 3b · N=3,533
FLOW (Perkovic 2024, NEJM, PMID 38785209) is the first GLP-1 receptor agonist trial designed and powered for a primary kidney outcome. The trial randomized 3,533 adults with type 2 diabetes and chronic kidney disease to once-weekly semaglutide 1.0 mg or placebo and was halted early for efficacy after a planned interim analysis. Over a median 3.4 years of follow-up, semaglutide reduced the primary composite of major kidney-disease events and cardiovascular or kidney death by 24% versus placebo. The result drove the January 2025 FDA Ozempic label expansion for reducing the risk of kidney-disease progression and kidney failure in adults with type 2 diabetes and chronic kidney disease.
Last verified 2026-05-28
SURMOUNT-2 deep dive: tirzepatide 10/15 mg in obesity plus type 2 diabetes
SURMOUNT-2 · 3 · N=938
SURMOUNT-2 randomized 938 adults with obesity and type 2 diabetes to once-weekly tirzepatide 10 mg, 15 mg, or placebo for 72 weeks. The 15-mg arm lost a mean 14.7% of body weight on the treatment-regimen estimand versus 3.2% with placebo, and dropped HbA1c by 2.22 percentage points from a mean baseline of 8.02%. Nearly 87% of 15-mg participants reached at least 5% weight loss and 52% reached 15%, while 91% hit an HbA1c below 7%. The trial answered the question SURMOUNT-1 left open — does tirzepatide work for weight loss when diabetes is on board? — and underpinned Zepbound's positioning for the obesity-plus-T2D population.
Last verified 2026-05-28
STEP-2 trial deep-dive: semaglutide 2.4 mg in obesity + type 2 diabetes (Davies 2021 Lancet)
STEP-2 · Phase 3 · N=1,210
STEP-2 is the companion to STEP-1 — the pivotal trial that established once-weekly semaglutide 2.4 mg for adults with overweight or obesity who also have type 2 diabetes. Novo Nordisk randomized 1,210 adults with BMI ≥27 and HbA1c 7-10% to semaglutide 2.4 mg, semaglutide 1.0 mg (the Ozempic dose), or matching placebo for 68 weeks, with monthly lifestyle counseling in every arm. Mean weight loss at week 68 was −9.6% on the 2.4 mg dose versus −7.0% on 1.0 mg and −3.4% on placebo, with HbA1c falling by 1.6 percentage points on both active doses. The trial provided the regulatory case that Wegovy works in patients with T2D and informed why the obesity-dose effect on weight is blunted, but not erased, by diabetes.
Last verified 2026-05-28
STEP-3 trial deep-dive: semaglutide 2.4 mg plus intensive behavioral therapy (Wadden 2021 JAMA)
STEP-3 · Phase 3a · N=611
STEP-3 (Wadden 2021, JAMA, PMID 33625476) is the pivotal trial that asked whether semaglutide 2.4 mg adds anything when patients are already enrolled in a maximal lifestyle program. Both arms received 30 in-person intensive behavioral therapy visits with a registered dietitian over 68 weeks, a 1000-1200 kcal/day meal-replacement low-calorie diet for the first 8 weeks, and structured physical activity that ramped from 100 to 200 minutes per week. On top of that, semaglutide added 10.3 percentage points of additional weight loss versus placebo (-16.0% vs -5.7%). The result is the foundation for insurance prior-authorization rules that require concurrent lifestyle programs and the clinical case that GLP-1 therapy and behavioral therapy are additive, not redundant.
Last verified 2026-05-28
REWIND trial deep-dive: dulaglutide cuts MACE 12% in T2D, mostly primary prevention
REWIND · Phase 3 · N=9,901
REWIND is the largest and longest GLP-1 cardiovascular outcomes trial ever conducted — 9,901 adults with type 2 diabetes followed a median 5.4 years, with the unique distinction that 69% had no established cardiovascular disease at baseline. Weekly dulaglutide 1.5 mg reduced the primary three-point MACE composite by 12% versus placebo (HR 0.88, 95% CI 0.79-0.99, P=0.026). Unlike LEADER and SUSTAIN-6, which enrolled mostly secondary-prevention populations, REWIND tested whether GLP-1 agonism could prevent first cardiovascular events in lower-risk T2D patients — and the answer was yes, with effect sizes that held up in both primary- and secondary-prevention subgroups.
Last verified 2026-05-28
AWARD-7 deep-dive: dulaglutide vs insulin glargine in T2D with moderate-to-severe CKD
AWARD-7 · Phase 3 · N=577
AWARD-7 is the first phase-3 GLP-1 receptor agonist trial designed specifically for adults with type 2 diabetes and moderate-to-severe chronic kidney disease (eGFR 15 to <60 mL/min/1.73 m²). Eli Lilly randomized 577 participants to once-weekly dulaglutide 1.5 mg, dulaglutide 0.75 mg, or daily insulin glargine titrated to fasting plasma glucose, all layered on prandial insulin lispro, for 52 weeks. Both dulaglutide doses met non-inferiority versus glargine on the HbA1c primary endpoint at 26 weeks and produced less eGFR decline, lower urinary albumin-to-creatinine ratio, weight loss (rather than weight gain), and roughly two-thirds fewer hypoglycemic events at week 52. The trial supplied the kidney-specific evidence base behind dulaglutide's label use in advanced CKD and seeded later kidney-outcome programs.
Last verified 2026-05-28
SURMOUNT-3 deep dive: tirzepatide after intensive lifestyle intervention
SURMOUNT-3 · 3 · N=579
SURMOUNT-3 asked the question every patient and payer wants answered: does tirzepatide still work after someone has already lost weight on lifestyle alone? Eli Lilly enrolled 806 adults with obesity into a 12-week intensive lifestyle intervention, kept the 579 who lost at least 5% of their weight, and randomized them 1:1 to tirzepatide (titrated to max-tolerated 10 mg or 15 mg) or placebo for 72 more weeks of treatment, both groups continuing the lifestyle program. From the randomization point, tirzepatide drove an additional 18.4% mean weight loss versus a 2.5% regain on placebo — a placebo-subtracted 20.8 percentage points. Total weight loss across the lead-in and randomized phases reached roughly 26% on tirzepatide. The trial directly parallels STEP-3 (semaglutide plus intensive behavioral therapy) and is the strongest evidence against the argument that GLP-1 medications only work for people who have not yet tried lifestyle changes.
Last verified 2026-05-28
SUSTAIN-7 deep-dive: semaglutide vs dulaglutide once-weekly in T2D (Pratley 2018)
SUSTAIN-7 · Phase 3b · N=1,201
SUSTAIN-7 (Pratley 2018 Lancet Diabetes Endocrinol, PMID 29397376) is the first registrational head-to-head trial of two once-weekly GLP-1 receptor agonists. Novo Nordisk randomized 1,201 adults with type 2 diabetes inadequately controlled on metformin 1:1:1:1 to once-weekly subcutaneous semaglutide 0.5 mg, dulaglutide 0.75 mg, semaglutide 1.0 mg, or dulaglutide 1.5 mg for 40 weeks in an open-label design. At both the low-dose and high-dose comparisons, semaglutide cut HbA1c roughly 0.4 percentage points more than dulaglutide and reduced body weight by an additional 2.3 to 3.5 kg, with broadly similar gastrointestinal tolerability. The trial provided the regulatory and clinical basis for positioning semaglutide as the strongest A1C-reducing GLP-1 in the class.
Last verified 2026-05-28
AMPLITUDE-O trial deep-dive: efpeglenatide CV outcomes in T2D (Gerstein 2021 NEJM)
AMPLITUDE-O · Phase 3 · N=4,076
AMPLITUDE-O (Gerstein 2021, NEJM, PMID 34215025) is the cardiovascular outcomes trial that proved an exendin-based GLP-1 receptor agonist could cut MACE in high-risk type 2 diabetes — and the trial whose drug was then shelved. Across 4,076 adults with established cardiovascular disease or current kidney disease plus at least one CV risk factor, weekly subcutaneous efpeglenatide at 4 or 6 mg reduced the three-point MACE composite by 27% versus placebo over a median follow-up of 1.8 years, the shortest of any positive GLP-1 CVOT. A clear dose-response was reported (Gerstein 2023, Circulation, PMID 36802715): the 6 mg arm drove most of the benefit with a 35% MACE reduction, while the 4 mg arm showed an 18% directional reduction. The kidney composite fell 32%. Sanofi nonetheless discontinued efpeglenatide development before regulatory submission, leaving AMPLITUDE-O as a load-bearing class-effect paper for a drug that never reached patients.
Last verified 2026-05-28
SURMOUNT-CN deep dive: tirzepatide in Chinese adults with obesity (Zhao 2024 JAMA)
SURMOUNT-CN · Phase 3 · N=210
SURMOUNT-CN randomized 210 Chinese adults with obesity (BMI ≥28, or ≥24 with a weight-related comorbidity) 1:1:1 to once-weekly tirzepatide 10 mg, 15 mg, or placebo for 52 weeks at 29 centers in China. The 15-mg arm lost a mean 17.5% of body weight versus 2.3% with placebo (treatment difference −15.1 percentage points; P<0.001), and 85.8% of 15-mg participants achieved ≥5% weight loss. The trial used the China-specific BMI cutoffs (≥28 for obesity; ≥24 for overweight) recommended for Asian populations, supplied 95.7% trial completion, and reported gastrointestinal adverse events as the most frequent treatment-emergent events, with treatment-discontinuation rates under 5%.
Last verified 2026-05-28
HARMONY OUTCOMES deep-dive: albiglutide MACE result for a shelved GLP-1 (Hernandez 2018)
HARMONY OUTCOMES · Phase 3 (registered as Phase 4 on ClinicalTrials.gov; conducted as a post-approval cardiovascular outcomes trial) · N=9,463
HARMONY OUTCOMES (Hernandez 2018, Lancet, PMID 30291013) is the cardiovascular outcomes trial for albiglutide, the once-weekly GLP-1 receptor agonist GSK marketed briefly as Tanzeum in the United States and Eperzan in Europe. GSK announced in July 2017 that it would withdraw the drug for commercial reasons rather than safety, and finished pulling the product from global markets by July 2018. The trial was already running, was kept going on contractual obligation to enrolled participants, and read out three months after withdrawal completed. Across 9,463 adults with type 2 diabetes and established cardiovascular disease, albiglutide reduced three-point MACE by 22% versus placebo (hazard ratio 0.78, P=0.0006 for superiority) over a median 1.6 years. The result was driven mainly by a reduction in myocardial infarction. HARMONY OUTCOMES still counts as one of the four positive MACE trials that anchor the GLP-1 cardiovascular class effect, even though the drug behind it never reached patients again.
Last verified 2026-05-28
ELIXA trial deep-dive: lixisenatide CV outcomes after ACS (Pfeffer 2015)
ELIXA · Phase 3 · N=6,068
ELIXA (Pfeffer 2015, NEJM, PMID 26630143) was the first cardiovascular outcomes trial completed for any GLP-1 receptor agonist. Across 6,068 adults with type 2 diabetes who had been hospitalized for a myocardial infarction or unstable angina within the prior 180 days, once-daily subcutaneous lixisenatide produced a hazard ratio of 1.02 for the four-point composite of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina over a median 25 months. The result met the FDA noninferiority bar but did not show superiority, setting the historical baseline against which LEADER, SUSTAIN-6, REWIND, AMPLITUDE-O, and SELECT would later be compared.
Last verified 2026-05-28
SUMMIT trial deep-dive: tirzepatide for HFpEF and obesity (Packer 2025 NEJM)
SUMMIT · Phase 3 · N=731
SUMMIT is the pivotal phase-3 trial that established tirzepatide as the first GLP-1/GIP dual agonist to reduce cardiovascular death and worsening heart failure events in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. This deep-dive walks through both primary endpoints (composite CV outcome + KCCQ-CSS), every reported secondary endpoint — 6-minute walk distance, hsCRP, body weight, NT-proBNP, blood pressure, troponin T, eGFR — with the actual numbers from the Packer 2025 NEJM publication and the Borlaug 2025 Nat Med mechanistic companion, plus adverse events, the diabetes subgroup analysis, and FAQs about how SUMMIT compares with STEP-HFpEF and what the result means for Wegovy patients.
Last verified 2026-05-28
STEP-HFpEF trial deep-dive: semaglutide 2.4 mg in HFpEF + obesity (Kosiborod 2023 NEJM)
STEP-HFpEF · Phase 3 · N=529
STEP-HFpEF is the first phase-3 trial to show that a GLP-1 receptor agonist can meaningfully improve symptoms, physical function, and inflammation in heart failure with preserved ejection fraction. Kosiborod and colleagues randomized 529 adults with HFpEF (LVEF ≥45%) and obesity (BMI ≥30) to once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Both co-primary endpoints — change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and percentage change in body weight — were met with large effect sizes. The trial reframed HFpEF as a disease where targeting cardiometabolic biology produces benefits on par with the symptomatic effects of SGLT2 inhibitors, and it underpinned the Wegovy heart-failure label additions in the obesity-HFpEF population.
Last verified 2026-05-28
EXSCEL trial deep-dive: exenatide once-weekly CV outcomes in T2D (Holman 2017)
EXSCEL · Phase 3/4 · N=14,752
EXSCEL (Holman 2017, NEJM, PMID 28910237) is one of the largest GLP-1 cardiovascular outcomes trials ever run: 14,752 adults with type 2 diabetes randomized to once-weekly exenatide 2 mg (Bydureon) or matching placebo across 35 countries, followed a median 3.2 years. The primary three-point MACE composite reached non-inferiority but narrowly missed superiority (HR 0.91, 95% CI 0.83 to 1.00, P=0.06). The neutral result, sitting between the positive LEADER and SUSTAIN-6 trials and the neutral ELIXA trial, helped establish that GLP-1 cardiovascular benefit is molecule-dependent rather than a uniform class effect. Bydureon was discontinued in the U.S. market in 2024.
Last verified 2026-05-28
SCALE Teens deep-dive: liraglutide 3.0 mg in adolescents (Kelly 2020 NEJM)
SCALE Teens · Phase 3 · N=251
SCALE Teens (Kelly 2020, NEJM, PMID 32233338) is the pivotal phase-3 trial that supported the December 2020 FDA pediatric indication for Saxenda (liraglutide 3.0 mg) in adolescents ages 12 and older with obesity. Across 251 participants randomized 1:1 to once-daily subcutaneous liraglutide 3.0 mg or placebo on top of lifestyle therapy for 56 weeks, liraglutide produced a 0.22-point greater reduction in BMI standard-deviation score, a 4.64-percentage-point greater BMI drop, and a 5.01-percentage-point greater relative weight loss versus placebo, with 43.3% of liraglutide-treated adolescents reaching at least 5% BMI reduction. The 26-week off-drug follow-up documented partial rebound, a pattern later confirmed across the GLP-1 class.
Last verified 2026-05-28
PIONEER 6 deep-dive: oral semaglutide cardiovascular outcomes (Husain 2019 NEJM)
PIONEER 6 · Phase 3a · N=3,183
PIONEER 6 (Husain 2019, NEJM, PMID 31185157) is the first cardiovascular-outcomes trial of an oral GLP-1 receptor agonist. Across 3,183 adults with type 2 diabetes at high cardiovascular risk, oral semaglutide titrated to 14 mg daily met the regulatory bar for cardiovascular safety against placebo over a relatively short median 15.9 months. The primary three-point MACE composite produced a hazard ratio of 0.79 (95% CI 0.57–1.11), which cleared non-inferiority (P<0.001) but did not reach superiority. The headline-grabbing secondary results were a 51% reduction in cardiovascular death and a 49% reduction in all-cause mortality — both statistically significant in pre-specified hierarchical testing — alongside nominally lower nonfatal MI and stroke rates that did not individually reach significance.
Last verified 2026-05-28
SCALE Maintenance deep-dive: liraglutide 3.0 mg after diet-induced weight loss (Wadden 2013)
SCALE Maintenance · Phase 3 · N=422
SCALE Maintenance is the Saxenda equivalent of STEP-4 — the trial that tested whether liraglutide 3.0 mg can hold a weight loss already produced by diet. Novo Nordisk enrolled non-diabetic adults with overweight or obesity, put everyone through a 4-12 week 1,200-1,400 kcal/day low-calorie-diet run-in, and then randomized the 422 participants who lost at least 5% of screening weight to once-daily subcutaneous liraglutide 3.0 mg or placebo for 56 weeks alongside a 500 kcal/day deficit diet and exercise counseling. The primary endpoint was percentage weight change from randomization to week 56. Participants on liraglutide lost an additional 6.2% on top of the run-in loss vs 0.2% on placebo, with 50.5% achieving a further ≥5% loss vs 21.8%. Waist circumference, blood pressure, and lipid markers all shifted in the same direction.
Last verified 2026-05-28
STEP 7 deep dive: semaglutide 2.4 mg in East Asian adults (Mu 2024 Lancet)
STEP 7 · Phase 3a · N=375
STEP 7 randomized 375 adults with overweight or obesity (BMI thresholds set to Asian-population cutoffs) 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 44 weeks at 23 centers in China, Hong Kong, South Korea, and Brazil. Mean body-weight change was -12.1% with semaglutide versus -3.6% with placebo (treatment difference -8.5 percentage points; 95% CI -10.2 to -6.8; p<0.0001), and 85% of the semaglutide group reached the 5% weight-loss threshold versus 31% on placebo (odds ratio 13.1). Unlike the multinational STEP 1 trial, STEP 7 ran for only 44 weeks and enrolled participants with or without type 2 diabetes, broadening the generalizability question for the East Asian population that anchored the design.
Last verified 2026-05-28
SCALE Diabetes deep-dive: liraglutide 3.0 mg in T2D + obesity (Davies 2015 JAMA)
SCALE Diabetes · Phase 3 · N=846
SCALE Diabetes is the pivotal trial that established liraglutide 3.0 mg in the type 2 diabetes + obesity subset. Novo Nordisk randomized 846 adults with T2D and BMI at least 27 to once-daily subcutaneous liraglutide 3.0 mg, liraglutide 1.8 mg (the diabetes-dose comparator), or placebo for 56 weeks alongside a 500 kcal/day deficit diet and exercise counseling. Mean weight loss was 6.0% on liraglutide 3.0 mg vs 4.7% on 1.8 mg vs 2.0% on placebo; 54.3% on 3.0 mg achieved at least 5% loss vs 21.4% on placebo. HbA1c fell by 1.3 percentage points on 3.0 mg vs 0.3 on placebo, with concordant improvements in fasting glucose, waist circumference, and systolic blood pressure. Davies and colleagues published the primary results in JAMA on August 18, 2015.
Last verified 2026-05-28