In May, Eli Lilly released its phase 3 clinical trial results for retatrutide, which have generated considerable excitement across the endocrinology and obesity medicine communities. 

The pivotal TRIUMPH-1 trial demonstrated an average weight loss of 28.3% of body weight at 80 weeks with the highest studied dose, reaching levels historically associated with bariatric surgery. Subsequent readouts from the TRIUMPH program, including  detailed findings published in September, have continued to showcase powerful efficacy across diverse populations. 

However, as these potent therapies advance toward potential regulatory review, obesity medicine specialists face an emerging clinical reality: Many prospective candidates will not be starting treatment from scratch. Many may arrive to retatrutide therapy having already optimized semaglutide or tirzepatide. Some may be facing the challenge that clinicians are increasingly describing — the GLP-1 plateau.

Could adding glucagon receptor agonism to existing GLP-1 and GIP pathways provide the biological leverage needed to break these plateaus? 

The Biological Rationale: Bypassing the Energy Expenditure Ceiling 

Single- and dual-incretin therapies like semaglutide and tirzepatide primarily target energy intake by inducing central satiety and delaying gastric emptying. However, chronic caloric restriction triggers metabolic adaptation, a response where the central nervous system downregulates energy expenditure and upregulates counterregulatory mechanisms to conserve energy stores.

"Adding glucagon receptor activation may offer a complementary mechanism beyond appetite reduction," said Gevork Tatarian, MD, a cosmetic surgeon and founder of Elevé Cosmetic Surgery in Coral Gables, Florida. "As patients lose weight, their energy requirements decline, and metabolic adaptation can make further weight loss more difficult. Glucagon signaling may influence energy expenditure and fat metabolism, potentially addressing part of that adaptation."

James Chao, MD, co-founder and chief medical officer of VedaNu Wellness in San Diego, said the drug's impact on the liver is what to watch. 

"Glucagon can help stimulate the metabolism and increase lipolysis in the liver," Chao said. "GLP-1 and GIP primarily reduce appetite, so once your calorie intake has plateaued the body is going to lower your energy expenditure. Phase 2 data was exciting with regards to liver fat, but whether it can help break through a plateau, we just don't know."

In addition to brown tissue thermogenesis and fat burning in the liver, Vishal Dubey, MPharm, researcher and manager of scientific and medical affairs at India-based supplement company Nutricult, said glucagon receptor activation "stimulates mitochondrial substrate cycling and white adipose tissue catabolism, actively increasing resting energy expenditure." 

He said that while standalone glucagon activation carries a hyperglycemic liability, co-infused GLP-1 and GIP components stimulate glucose-dependent insulin secretion, neutralizing potential hyperglycemia and allowing clinicians to harness glucagon's catabolic power safely.

However, experts urged caution against overinterpreting theoretical mechanisms. 

"A promising mechanism is not the same as a proven switching strategy. Retatrutide's weight-loss results are encouraging, but they do not yet establish that it reliably reverses plateaus in patients taking semaglutide or tirzepatide," said Tatarian. "Retatrutide remains investigational and is not FDA-approved, so it is not an option for routine clinical prescribing."

Interpreting Phase 3 Data and Prior Treatment History 

Phase 3 trials, such as the TRIUMPH program, have demonstrated headline-making numbers, including the average weight loss of 28.3% of body weight at 80 weeks in TRIUMPH-1, sponsor-reported reductions of 20.8% in the diabetes cohort of the TRIUMPH-2 study, and 22.6% in the severe obesity with cardiovascular disease population studied in the TRIUMPH-3 trial. However, translating these findings to patients with prior GLP-1 exposure requires careful context.

"The major limitation is that these results do not tell us how much additional weight a patient will lose after plateauing on semaglutide or tirzepatide," Tatarian said. "TRIUMPH-1 excluded patients who had taken weight-loss medications within the preceding 90 days, so it was not designed as a direct transition study. Substantial weight loss from a trial's baseline should not be interpreted as the same amount of additional weight loss after another medication."

Experts said that clinicians must anticipate that patients transitioning from an existing incretin will experience a longer initial waiting time for the secondary medication to produce effects as compared to incretin-naive participants. Additionally, while prior exposure provides cross-tolerance to baseline gastrointestinal side effects, it does not fully insulate patients from adverse events during aggressive titration or when a brand-new receptor pathway is introduced. 

Navigating Tolerability, Safety, and Chronotropic Risk 

Moving from a dual to a triple agonist alters the patient's physiological safety profile. While gastrointestinal adverse events remain important, clinical data from TRIUMPH-2 show that the highest studied dose was associated with nausea in 28.0% of participants, diarrhea in 33.6% of participants, and vomiting in 15.7% of participants. Chao said that while trial data show increased gastrointestinal side effects with the triple agonist, they were generally mild to moderate and manageable when starting at lower doses.

"Those findings reinforce the importance of careful titration and monitoring, but they do not directly quantify how tolerability changes when someone transitions from tirzepatide," Tatarian said. 

Heart rate also warrants close attention, according to clinicians. Phase 2 trials identified dose-dependent increases that peaked around week 24 and subsequently declined. 

"I think we will see more increased heart rate," Chao said. "So, if you're already on a dual agonist and your heart rate is slightly higher, adding another could be detrimental." 

Specialists emphasized that ongoing clinical monitoring is preferable over assuming that greater weight loss automatically translates to an improved cardiovascular safety profile, particularly because available TRIUMPH-3 cardiovascular event analyses have not yet established a reduction in major adverse cardiovascular events.

Strategic Sequencing for the Treatment Lifecycle 

To avoid exhausting the available pharmacological toolkit too early in a patient's decades-long disease management lifecycle, specialists advocated for a personalized, goal-oriented framework rather than a rigid ladder.

Clinicians said to reject the mandatory escalation mindset; Chao said that many patients reach their health goals on GLP-1s and that holding back on triple agonists "preserves a vital fallback option."

"I would not frame treatment as a ladder that every patient must climb from a single agonist to a dual agonist and eventually to a triple agonist," Tatarian said. "The goal is to select a treatment that addresses the patient's obesity-related complications, provides meaningful benefit, is tolerated, and can be sustained." 

While fast weight loss is attractive and incentivizes patients, long-term management and retention are really the name of the game, according to clinicians. Before switching to a triple agonist, experts said clinicians should confirm that current treatments have undergone adequate trials, address adherence barriers, and recognize that maintaining health improvements is just as valuable as generating additional scale loss. 

"Keep in mind if you stop your medication, you can regain two thirds of your weight loss in 1 year. Same goes for surgery, if your patient plateaus you will have to re-evaluate their body contouring needs," Chao said. "People never talk about this!"

The experts cited in this article had no relevant disclosures.