Key points
- CagriSema (REDEFINE 1, 3,417 adults): 20.4% weight reduction vs 3.0% with placebo under the treatment-policy estimand; 22.7% under the trial-product estimand [1][9].
- Orforglipron, oral and non-peptide: 11.2% reduction at 72 weeks (ATTAIN-1). FDA approved it in April 2026 [3][10].
- MariTide, monthly: 12.3% to 16.2% reductions at 52 weeks in phase 2 (cohort without diabetes), with frequent GI adverse events [4].
- Mazdutide (China, GLORY-1): 11.0% and 14.0% reductions at 48 weeks under the treatment-policy estimand [6].
US status (October 2026): See the peptide status tracker.
Check the estimand before you compare any two obesity drugs. The same trial can produce two honest numbers, and the larger one is usually the one in the press release.
The estimand decides the headline number
Modern obesity trials report two numbers. The treatment-policy estimand analyzes everyone randomized, including people who stopped the drug. It is closer to real-world practice. The trial-product (efficacy) estimand estimates the effect if everyone had stayed on treatment. It gives bigger numbers. Topline announcements sometimes highlight the second, such as CagriSema’s 22.7% [9]. The REDEFINE 1 and GLORY-1 publications use the first as the primary analysis [1][6].
CagriSema performed well, below expectations
In REDEFINE 1 (3,417 adults), cagrilintide plus semaglutide was associated with a 20.4% reduction vs 3.0% with placebo (treatment policy), with GI events in 79.6% vs 39.9% [1]. The trial-product estimand was 22.7% [9]. In type 2 diabetes (REDEFINE 2, 1,206 adults), the reductions were 13.7% vs 3.4% [2].
- 20.4%: CagriSema, treatment policy (REDEFINE 1) [1]
- 11.2%: oral orforglipron at 72 weeks [3]
- 16.2%: monthly MariTide, best arm at 52 weeks [4]
For the approved anchors these combinations are measured against, see the semaglutide and tirzepatide status pages.
Orforglipron is the first non-peptide GLP-1 pill
Orforglipron is a small molecule, not a peptide, that activates the GLP-1 receptor orally. In ATTAIN-1 (3,127 adults), the 36 mg dose was associated with an 11.2% reduction vs 2.1% at 72 weeks. Discontinuation for adverse events was 5.3 to 10.3% vs 2.7% [3]. In ACHIEVE-4 it was non-inferior to insulin glargine on cardiovascular events (HR 0.84) [5]. FDA approved it on April 1, 2026 [10].
MariTide, survodutide and mazdutide each come with caveats
- MariTide (maridebart cafraglutide), monthly: 12.3% to 16.2% reductions at 52 weeks vs 2.5% in the obesity cohort without diabetes (465 of the 592 adults in this phase 2 trial). GI adverse events were common, less so with dose escalation and a lower starting dose [4].
- Survodutide (SYNCHRONIZE-1, 725 adults): 12.2% and 13.0% reductions vs 5.4% at 76 weeks (treatment-regimen estimand), with GI events in 80.9 to 89.7% vs 47.9% with placebo [7]. The 5.4% placebo drop is a reminder that trial context matters too.
- Mazdutide (GLORY-1, China): 11.0% and 14.0% reductions vs a 0.3% gain at 48 weeks under the treatment-policy estimand [6]. At 9 mg (GLORY-2), the reduction was 16.65% vs 1.50% at 60 weeks, with vomiting in 53.1% [8].
What this means for your clinic
Comparing numbers across drugs without checking the estimand, duration and trial population leads to wrong conclusions [1][6]. When a patient brings a headline figure, ask which analysis it came from.
The second message is about supply. Most of these molecules are not yet FDA-approved [10], and what is sold under those names outside the regulated chain does not have the controls of the trial products [11]. A “research use only” label does not change that. See what that label means and the compounded GLP-1 rules after the shortage. If you run a weight program, our weight management service is built on approved products.
References
- Garvey WT, et al. Coadministered cagrilintide and semaglutide in adults with overweight or obesity (REDEFINE 1). N Engl J Med. 2025;393(7):635-647. PMID 40544433. Link
- Davies MJ, et al. Cagrilintide-semaglutide in adults with overweight or obesity and type 2 diabetes (REDEFINE 2). N Engl J Med. 2025;393(7):648-659. PMID 40544432. Link
- Wharton S, et al. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment (ATTAIN-1). N Engl J Med. 2025;393(18):1796-1806. PMID 40960239. Link
- Jastreboff AM, et al. Once-monthly maridebart cafraglutide for the treatment of obesity – a phase 2 trial. N Engl J Med. 2025;393(9):843-857. PMID 40549887. Link
- Klein KR, et al. Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial. Lancet. Published online 30 September 2026. doi:10.1016/S0140-6736(26)01865-9. PMID 42815506. Link
- Ji L, et al. Once-weekly mazdutide in Chinese adults with obesity or overweight (GLORY-1). N Engl J Med. 2025;392(22):2215-2225. PMID 40421736. Link
- le Roux CW, et al. Survodutide Once Weekly for the Treatment of Adults with Obesity (SYNCHRONIZE-1). N Engl J Med. 2026;395(8):776-787. PMID 42253238. Link
- Gao L, et al. Treatment With 9-mg Mazdutide for Weight Reduction in Chinese Adults With Obesity: The GLORY-2 Randomized Clinical Trial. JAMA. 2026;336(5):377-388. PMID 42251595. Link
- Iapoce C. CagriSema achieves 22.7% weight loss in phase 3 REDEFINE 1 trial. HCPLive. 20 December 2024. Link
- U.S. Food and Drug Administration. Novel Drug Approvals for 2026. Link
- U.S. Food and Drug Administration. FDA’s concerns with unapproved GLP-1 drugs used for weight loss. Updated 1 October 2026. Link
This is general information, not medical or legal advice. Rules vary by state and change. Confirm your own facts with counsel.