Lancet & Nat Med
GLP-1 weight loss can be maintained on lower dose
Clinical Takeaway: Patients who have lost weight on injectable tirzepatide or semaglutide do not have to stay on the maximum injectable dose forever to keep most of the benefit. A reduced dose or a switch to oral orforglipron preserves a meaningful share of the loss, with the max dose offering the strongest protection.
Initial weight loss with GLP-1 and dual GIP/GLP-1 receptor agonists is now well established, but persistence on injectable therapy at the maximum dose is the real-world bottleneck. Patients want simpler regimens, lower costs, and fewer injections. Two trials published simultaneously in The Lancet and Nature Medicine test whether the maintenance phase can be lighter than the induction phase without giving up the gains.
The Lancet trial, SURMOUNT-MAINTAIN, asked whether a lower dose of the same drug could enable patients to hold on to the loss. The trial enrolled 441 adults who took tirzepatide at the maximum tolerated dose (10 mg or 15 mg) for 60 weeks. The 378 participants who had lost at least 5% of body weight were then randomized to continue at max dose, drop to 5 mg, or switch to placebo for 52 weeks. Patients staying on the max dose lost an additional 0.2 kg (0.4 lb) on average. Patients dropped to 5 mg gained back 6 kg (13 lb). Patients on placebo gained back 13 kg (29 lb), often heading toward pretreatment weight.
Among patients who plateaued before randomization, the dose-response on maintenance was clear: 77.5% on max dose preserved at least 80% of their loss, compared with 42.4% on 5 mg and 10.4% on placebo. The odds of holding that 80% mark were roughly seven times higher on max dose than placebo, and four times higher on 5 mg than placebo.
The Nature Medicine trial, ATTAIN-MAINTAIN, asked a different question: can patients switch from an injectable to a daily pill? It enrolled 376 patients who had completed the SURMOUNT-5 head-to-head trial of injectable tirzepatide versus injectable semaglutide, then randomized them to once-daily oral orforglipron or placebo. The trial ran as two separate cohorts based on which injectable patients had been on.
Among patients who plateaued, the tirzepatide-to-orforglipron group preserved 74.7% of their loss versus 49.2% on placebo. The semaglutide-to-orforglipron group preserved 79.3% versus 37.6% on placebo. Patients switching from semaglutide held on to almost all of their loss on the pill, while those switching from the more potent tirzepatide saw a small additional regain of roughly 5 kg (11 lb) on average.
Cardiometabolic improvements tracked the weight pattern across both trials. Continued max-dose tirzepatide preserved gains in waist circumference, blood pressure, lipids, and HbA1c. Reducing the dose held those benefits to a lesser degree. Oral orforglipron preserved cardiometabolic improvements in both ATTAIN-MAINTAIN cohorts, with HbA1c, fasting glucose, and lipid markers remaining at the improved levels achieved with the initial injectable.
Both trials were funded by Eli Lilly, which manufactures tirzepatide (Zepbound) and orforglipron (Foundayo). Several authors have financial relationships with the company.
Together, the trials reframe weight-loss maintenance as a menu rather than a binary. Staying on the maximum injectable dose offers the strongest protection against regain. A lower injectable dose works for some patients. An oral GLP-1 works for others. What does not work is stopping. In both trials, the placebo arms regained substantial weight by the end of the maintenance phase.
"These medicines can be used for long-term maintenance today," said Louis Aronne, MD, senior author on the ATTAIN-MAINTAIN paper. "Weight regain remains one of the biggest challenges in obesity care, and is often the result of treatment interruptions that cause biology to work against patients, undoing the progress they've made."
Sources: Horn DB. Lancet. 2026 May 12. Tirzepatide for maintenance of bodyweight reduction in people with obesity in the USA (SURMOUNT-MAINTAIN); Aronne LJ. Nat Med. 2026 May 12. Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial