A common question from patients who have lost weight on an injectable GLP-1 receptor agonist such as Wegovy (semaglutide) or Zepbound (tirzepatide) is what to do next. Stopping these medications typically leads to rapid weight regain, yet some patients prefer to avoid ongoing injections due to convenience, cost, or cold storage requirements. Until now, there was no randomized trial evidence to guide providers on whether switching to an oral GLP-1 therapy could preserve the weight reduction achieved with injectable therapy.

The ATTAIN-MAINTAIN trial (N=376 | 52 weeks | double-blind, placebo-controlled) was the first clinical trial to examine this switch. Eligible participants had completed SURMOUNT-5, a 72-week head-to-head trial of tirzepatide versus semaglutide, with at least 5% weight loss and no diabetes. They were re-randomized 3:2 to once-daily orforglipron (starting at 12 mg, escalated every four weeks to 36 mg or maximum tolerated dose) or placebo, along with lifestyle counseling. The trial enrolled two independent cohorts: 205 participants who had been on tirzepatide (cohort 1) and 171 on semaglutide (cohort 2). The primary endpoint was the percent maintenance of SURMOUNT-5 weight loss at week 52 among participants with a weight plateau in the final weeks of SURMOUNT-5.

Among plateau participants, orforglipron was superior to placebo in both cohorts. In cohort 1, orforglipron maintained 74.7% of prior weight loss versus 49.2% with placebo (treatment difference 25.5 percentage points; 95% CI 14.5 to 36.5; P<0.001). In cohort 2, maintenance was 79.3% versus 37.6% (difference 41.7 percentage points; 95% CI 24.4 to 59.0; P<0.001). All key secondary endpoints were met, including the proportion maintaining at least 80% of prior weight loss (cohort 1: 43.7% vs 16.4%; cohort 2: 55.0% vs 6.9%; P<0.001 for both). Gastrointestinal events — nausea, constipation, vomiting, and diarrhea — were the most common adverse effects with orforglipron and were mostly mild to moderate. GI events in the first four weeks after the switch were low (10.5% and 9.5% in the two cohorts), suggesting that transitioning from injectable therapy directly to the 12 mg dose was generally well tolerated. Discontinuation due to adverse events occurred in 7.3% and 4.8% of orforglipron-treated participants versus 2.5% and 3.0% of placebo-treated participants.

ATTAIN-MAINTAIN provides the first randomized evidence to support switching from injectable to oral incretin therapy for weight-loss maintenance in patients without diabetes. For patients who wish to stop injections, orforglipron (Foundayo) preserved the majority of the weight loss achieved with tirzepatide or semaglutide over one year, with an acceptable safety profile. Study limitations include enrollment at US-only sites, a predominantly white population, a one-year follow-up period, and the absence of a comparator arm continuing injectable therapy. Providers should use the data to guide shared decision-making conversations, particularly for patients in whom long-term adherence to injectable therapy is a concern.

• Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial, Nat Med (2026) [PubMed abstract]
• Orforglipron (Foundayo) review