As retatrutide moves toward FDA submission, Jennifer Goldman, PharmD, breaks down the TRIUMPH-1 data—and what they mean for patient selection, dose escalation counseling, and positioning within the antiobesity pipeline.
In an interview with Pharmacy Times, Jennifer Goldman, PharmD, CDCES, BC‑ADM, FCCP, professor of pharmacy practice at Massachusetts College of Pharmacy and clinical pharmacist at Well Life, discussed the clinical implications of the pivotal phase 3 TRIUMPH-1 (NCT05929066) trial data for retatrutide, Eli Lilly's investigational once-weekly glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 receptor agonist (GLP-1 RA), and glucagon triple hormone receptor agonist.
The topline
What sets retatrutide apart from currently approved incretin-based therapies, Goldman explains, is its glucagon receptor agonism, which adds a mechanism of increased energy expenditure and hepatic fatty acid oxidation absent in dual GIP/GLP-1 agonists like tirzepatide (Mounjaro, Zepbound; Eli Lilly). This third receptor pathway may account for the drug's continued weight-loss trajectory without plateau through 80 weeks, as well as its robust cardiometabolic effects—including reductions in triglycerides, non–high-density lipoprotein cholesterol, systolic blood pressure, and high-sensitivity C-reactive protein (hsCRP) observed in TRIUMPH-1.
Goldman addresses how pharmacists and prescribers might position retatrutide within a stepwise treatment intensification model, what proactive patient counseling should look like given the novel adverse effect of dysesthesia, which patients may be better suited to the lower 4-mg maintenance dose, and why the absence of cardiovascular outcomes data remains an important caveat as the drug moves toward a regulatory submission anticipated in 2026.
Pharmacy Times: With retatrutide's triple GIP/GLP-1/glucagon mechanism now demonstrating bariatric-level weight loss in TRIUMPH-1, how do you anticipate pharmacists and prescribers will approach positioning it within the existing landscape of approved agents like tirzepatide and orforglipron—particularly for patients who haven't achieved adequate response to a dual agonist?
Jennifer Goldman, PharmD, CDCES, BC‑ADM, FCCP: The TRIUMPH-1 phase 3 data position retatrutide as a potential escalation therapy beyond currently approved agents, reporting up to 30.3% weight loss. From a pharmacy practice standpoint, the likely positioning will follow a stepwise intensification model. The currently available therapies include semaglutide (Ozempic, Wegovy; Novo Nordisk), tirzepatide, and orforglipron (Foundayo; Eli Lilly). Pharmacists and prescribers will likely consider retatrutide for patients who have not achieved clinically meaningful weight-loss thresholds on a dual GIP/GLP-1 agonist (or other options) or for patients with higher baseline BMI who may benefit from the additional glucagon receptor-mediated increase in energy expenditure and fatty acid oxidation. Retatrutide’s glucagon receptor agonism provides an additional pathway: increased hepatic fatty acid oxidation and energy expenditure that is absent in the other agents.
Pharmacy Times: The TRIUMPH-1 data show discontinuation rates up to 11.3% at the highest dose, along with dysesthesia as a novel adverse effect not commonly seen with existing GLP-1 therapies. From your clinical experience in cardiometabolic services, what patient education strategies should pharmacists prioritize when counseling patients on retatrutide's tolerability, and which patients may be better suited to the lower 4-mg maintenance dose?
Goldman: The tolerability profile of retatrutide requires proactive, anticipatory counseling that goes beyond the standard GLP-1 class education, particularly regarding the novel finding of dysesthesia/hyperesthesia and the importance of gradual dose escalation. In the phase 2 obesity trial (NCT04881760), discontinuation due to adverse events ranged from 6% to 16% across retatrutide dose groups vs 0% with placebo. The highest discontinuation rate was with 12 mg. Gastrointestinal (GI) adverse events were the most common reason for discontinuation and occurred primarily during dose escalation. Regarding dysesthesia/hyperesthesia, in the phase 2 obesity trial, this occurred in 7% of retatrutide-treated patients vs 1% with placebo, with higher rates at the higher doses. These events were mild to moderate, not related to the magnitude of weight loss, and none led to treatment discontinuation.2,3
Phase 2 data showed that even the 4-mg dose achieved clinically meaningful weight loss of 17.1% at 48 weeks, with 60% achieving 15% or greater body weight reduction. Candidates for the lower 4-mg maintenance dose include those with significant GI intolerance during escalation, older adults, or those with lower BMI who may be at risk of excessive weight loss; patients with a history of sensitivity to incretin-based therapies; and those with a favorable tolerability-efficacy balance.
Key patient education strategies pharmacists should prioritize would be:
Pharmacy Times: Beyond weight loss, TRIUMPH-1 demonstrated improvements in non–high-density lipoprotein cholesterol (non–HDL-C), triglycerides, systolic blood pressure, and hsCRP. How significant are these cardiometabolic benefits in the context of treating patients with complex comorbidities?
Goldman: The cardiometabolic improvements observed are highly significant and likely extend beyond what can be attributed to weight loss alone, particularly glucagon receptor-mediated effects on hepatic lipid metabolism. In the phase 2 type 2 diabetes trial (NCT04867785), retatrutide dose-dependently reduced triglycerides by up to 35%, non–HDL-C by up to 20.7%, and systolic blood pressure [BP] by up to 8.8 mm Hg at 36 weeks. In the phase 2 obesity trial, improvements in BP were clinically meaningful enough that 41% of participants in the combined 8-mg group and 30% in the 12-mg group discontinued at least 1 antihypertensive agent.2,4,5
Additionally, 72% of participants with prediabetes at baseline reverted to normoglycemia. Reductions in low-density lipoprotein cholesterol of approximately 20% with retatrutide may also reflect glucagon agonism-mediated effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) degradation, a mechanism distinct from the weight loss-driven lipid improvements seen with GLP-1 receptor agonists alone. There was a decrease in hsCRP reported in TRIUMPH-1, which is noteworthy, as systemic inflammation is a key driver of atherosclerotic cardiovascular disease and is increasingly recognized as a therapeutic target independent of traditional lipid lowering.1,4
For patients with complex cardiometabolic comorbidities such as obesity, dyslipidemia, hypertension, prediabetes or type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, these pleiotropic effects position retatrutide as potentially transformative. It is, however, important to understand that cardiovascular outcomes data are not yet available. The TRIUMPH-2 trial is specifically evaluating retatrutide in a population with established cardiovascular (CV) disease, and these results will be essential before definitive claims about CV risk reduction can be made. Semaglutide and dulaglutide have demonstrated CV event reduction in dedicated cardiovascular outcomes trials, and tirzepatide has demonstrated CV safety, but whether the addition of glucagon receptor agonism translates to CV benefit remains a critically important question.
