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After semaglutide: CagriSema, orforglipron, MariTide and the estimand trap

The next generation of obesity drugs arrives with double-digit numbers. But the same molecule can "lose" 20.4% or 22.7% depending on the estimand. How to read the results before they reach the clinic.

Published October 9, 2026 · 3 min read · 17 sources

What an estimand is and why it changes the number

Modern obesity trials report two numbers, following the estimand framework of the ICH E9(R1) addendum, in effect since 202012. The treatment-policy estimand analyzes everyone randomized, even if they 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 analysis16.

CagriSema: good, but below expectations

In REDEFINE 1 (3,417 adults), cagrilintide plus semaglutide was associated with −20.4% 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), −13.7% vs −3.4%2. For reference, semaglutide alone was associated with −14.9% vs −2.4% at 68 weeks in STEP 113, and cagrilintide, a long-acting amylin analog, with −6.0% to −10.8% vs −3.0% in its phase 2 trial (trial-product estimand)14.

−20.4%CagriSema, treatment policy (REDEFINE 1)1
−11.2%oral orforglipron at 72 weeks3
−16.2%monthly MariTide, best arm at 52 weeks4

Orforglipron: the first non-peptide 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 −11.2% vs −2.1% at 72 weeks; discontinuation for adverse events was 5.3–10.3% vs 2.7%3. In ACHIEVE-4 it was non-inferior to insulin glargine on cardiovascular events (HR 0.84)5. The FDA approved it on April 1, 202610. A pooled analysis of its phase 3 trials found no cases of drug-induced liver injury16.

MariTide, survodutide and mazdutide

  • MariTide (maridebart cafraglutide), monthly: −12.3% to −16.2% 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 dose4. The molecule links a GIP-receptor antagonist antibody to GLP-1 analogs; in phase 1, weight loss persisted for up to 150 days after the last dose15.
  • Survodutide (SYNCHRONIZE-1, 725 adults): −12.2% and −13.0% vs −5.4% at 76 weeks (treatment-regimen estimand), with GI events in 80.9–89.7% vs 47.9% with placebo7. The 5.4% placebo drop is a reminder that trial context matters too.
  • Mazdutide (GLORY-1, China): −11.0% and −14.0% vs +0.3% at 48 weeks with the treatment-policy estimand6. At 9 mg (GLORY-2), −16.65% vs −1.50% at 60 weeks, with vomiting in 53.1%8. China approved it in June 2025 for chronic weight management, based mainly on GLORY-117.

Why this matters to physicians

Comparing numbers across drugs without checking the estimand, duration and trial population leads to wrong conclusions16. And for the "research peptide" debate the message is different: most of these molecules are not yet FDA-approved10, and what is sold under those names outside the regulated chain does not have the controls of the trial products11.

Sources

  1. 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. PubMed 40544433 ↗
  2. 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. PubMed 40544432 ↗
  3. 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. PubMed 40960239 ↗
  4. 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. PubMed 40549887 ↗
  5. 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. PubMed 42815506 ↗
  6. 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. PubMed 40421736 ↗
  7. 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. PubMed 42253238 ↗
  8. 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. PubMed 42251595 ↗
  9. Iapoce C. CagriSema achieves 22.7% weight loss in phase 3 REDEFINE 1 trial. HCPLive. 20 December 2024. hcplive.com ↗
  10. U.S. Food and Drug Administration. Novel Drug Approvals for 2026. fda.gov ↗
  11. U.S. Food and Drug Administration. FDA's concerns with unapproved GLP-1 drugs used for weight loss. Updated 1 October 2026. fda.gov ↗
  12. European Medicines Agency. ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials (EMA/CHMP/ICH/436221/2017). Effective 30 July 2020. ema.europa.eu ↗
  13. Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384(11):989-1002. PubMed 33567185 ↗
  14. Lau DCW, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet. 2021;398(10317):2160-2172. PubMed 34798060 ↗
  15. Véniant MM, et al. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat Metab. 2024;6(2):290-303. PubMed 38316982 ↗
  16. Wharton S, et al. Hepatic safety of orforglipron in adults with obesity or overweight and/or type 2 diabetes: a pooled analysis of the orforglipron phase 3 clinical trials. Diabetes Obes Metab. 2026;28(9):8347-8358. PubMed 42338042 ↗
  17. Innovent Biologics (via BioSpace). Innovent announces mazdutide, first dual GCG/GLP-1 receptor agonist, received approval from China's NMPA for chronic weight management. 27 June 2025. biospace.com ↗

Informational article. It summarizes news, official statements and published studies; it is not medical or legal advice. Sources were checked on the publication date.

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