Orforglipron Maintains Weight Loss After Discontinuing Zepbound

Eli Lilly and Company recently announced detailed results from 2 late-phase trials, SURMOUNT-MAINTAIN (NCT06047548) and ATTAIN-MAINTAIN (NCT06584916), demonstrating that individuals with obesity can effectively maintain weight loss by transitioning to once daily oral orforglipron (Foundayo) or a lower dose of injectable tirzepatide (Zepbound) after using higher doses of injectable incretin therapy. These findings, presented at the European Congress on Obesity, address the significant clinical challenge of weight regain, which often follows treatment interruptions.¹

"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," Louis J. Aronne, M.D., FACP, DABOM, founder and chair emeritus of the American Board of Obesity Medicine, said in a news release. "These medicines can be used for long-term maintenance today, and results from SURMOUNT-MAINTAIN and ATTAIN-MAINTAIN provide additional evidence of their potential when switching from higher doses of injectable incretin therapy."

About the Trials

The ATTAIN-MAINTAIN trial specifically evaluated the efficacy of orforglipron, a nonpeptide oral glucagon-like peptide-1 (GLP-1) receptor agonist, in preserving weight loss after initial success with injectables. Participants who switched from a maximum tolerated dose of tirzepatide (Wegovy) to orforglipron maintained all but 0.9 kg of their previously achieved weight loss on average after 1 year.¹

Similarly, those who transitioned from a maximum tolerated dose of Zepbound to orforglipron maintained all but 5.0 kg of their prior loss during the same maintenance period. These results suggest that orforglipron can serve as a durable oral maintenance option for patients who have reached a weight plateau on injectable medications.¹

The SURMOUNT-MAINTAIN trial provided complementary data regarding dose reduction with injectable tirzepatide. Participants who reduced their Zepbound dose to a 5 mg maintenance level preserved all but 5.6 kg of their prior weight loss on average after 1 year.^1,2

In contrast, those who remained on their maximum tolerated dose of Zepbound for an additional year maintained all of their prior weight loss. These data help health care providers and pharmacists to have more nuanced shared decision-making conversations with patients regarding the balance between dose reduction and weight maintenance goals.^1,2

The Role of the Pharmacist

Pharmacists should note that orforglipron offers a unique pharmacokinetic profile compared with currently available oral GLP-1 therapies. Because it is a nonpeptide small molecule, it does not require the strict fasting or water intake protocols that often complicate patient adherence with other oral incretins. Patients can take the once daily tablet at any time of the day without food or water restrictions.^1-3

Although the standard starting dosage for treatment-naive patients is 0.8 mg with monthly titrations, the ATTAIN-MAINTAIN study utilized a direct transition from injectable therapy to a 12 mg dose of orforglipron. This higher starting dose for switchers was generally well-tolerated, with no participants requiring dose de-escalation due to gastrointestinal issues in the first 4 weeks.^1-3

Safety profiles for both medications remained consistent with previous phase 3 clinical studies. The most frequent adverse events reported were gastrointestinal in nature, including nausea, constipation, vomiting, and diarrhea. Pharmacists must be aware that orforglipron carries a boxed warning regarding the risk of thyroid C-cell tumors and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Additionally, patients should be advised that these medications are not intended for use in combination with other GLP-1 receptor agonists.^1-3

"Obesity is a chronic disease requiring long-term treatment, and patients need more options they can stay on for the long run," Kenneth Custer, PhD, executive vice president and president at Lilly Cardiometabolic Health, said in the news release.¹ "We are encouraged by the results of SURMOUNT-MAINTAIN and ATTAIN-MAINTAIN, which showed that both Zepbound and Foundayo, a once-daily oral GLP-1, provided durable weight loss maintenance. Lilly is committed to providing people with multiple treatment options as they navigate their weight-loss journey."

As the first new molecular entity cleared under the FDA's National Priority Voucher pilot program, orforglipron represents a significant shift toward scalable and oral obesity management. Its effectiveness in maintaining weight loss while improving cardiometabolic risk factors, such as blood pressure and lipid levels, highlights its potential role in long-term chronic disease care.^1-3

REFERENCES

1. Lilly's Foundayo and lower-dose Zepbound helped people maintain weight loss after switching from higher doses of injectable incretin therapy in two late-phase trials. News release. May 12, 2026. Accessed May 19, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-foundayo-and-lower-dose-zepbound-helped-people-maintain

2. Aronne LJ, Horn DB, le Roux CW, et al. Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial. Nat Med. Published online May 13, 2026. doi:10.1038/s41591-026-04386-7

3. Gallagher A. FDA Approves Orforglipron For Chronic Weight Management. Drug Topics. April 1, 2026. Accessed May 19, 2026. https://www.drugtopics.com/view/fda-approves-orforglipron-for-chronic-weight-management