Retatrutide Delivers Significant Hemoglobin A1C Reduction, Weight Loss in Phase 3 Type 2 Diabetes Trial

Eli Lilly and Company has announced positive top-line results from TRANSCEND-T2D-1 (NCT06354660), a phase 3 clinical trial evaluating retatrutide—an investigational, once-weekly, subcutaneous glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon triple hormone receptor agonist—in adults with type 2 diabetes (T2D).¹

The data show that retatrutide met its primary end point of superior hemoglobin A_1C (HbA_1C) reduction and all key secondary end points at 40 weeks compared with placebo. For pharmacists already counseling patients on semaglutide (Ozempic, Wegovy; Novo Nordisk) or tirzepatide (Zepbound, Mounjaro; Eli Lilly and Company), retatrutide represents a pharmacologically distinct agent that will require a clear explanation of how its triple-receptor mechanism differs from the dual and single agonists patients may already be familiar with.^1,2

TRANSCEND-T2D-1 Efficacy Results

The trial enrolled 537 adults with inadequate glycemic control on diet and exercise alone, with a mean T2D duration of 2.5 years, a mean baseline HbA_1C of 7.9%, and a mean body mass index of 35.8. Participants were randomly assigned 1:1:1:1 to retatrutide 4 mg, 9 mg, or 12 mg, or placebo, with all retatrutide arms initiating at 2 mg and escalating every 4 weeks to the target dose.¹

For the primary end point, participants achieved mean HbA_1C reductions of 1.7%, 2.0%, and 1.9% with retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with 0.8% with placebo. For the key secondary weight end point, the 12-mg group lost an average of 36.6 lb (16.8%) at 40 weeks, with no weight loss plateau observed through the end of the treatment period. Retatrutide also produced clinically meaningful improvements in non–high-density lipoprotein cholesterol, triglycerides, and systolic blood pressure, a cardiovascular risk profile that pharmacists managing complex cardiometabolic patients will want to note.¹

Building on Earlier Phase 2 Data

These phase 3 T2D results extend a compelling body of phase 2 evidence that pharmacists should be aware of as patient inquiries mount ahead of a potential approval. A 36-week phase 2 trial (NCT04867785) by Rosenstock et al, published in The Lancet, demonstrated dose-dependent HbA_1C reductions of up to 2.0% with retatrutide 12 mg in adults with T2D, with body weight reductions of up to 16.9%—reductions the investigators characterized as the largest ever reported for a glucose-lowering agent at that time.³

A separate phase 2 trial (NCT04881760) in adults with obesity but without T2D, published in the New England Journal of Medicine, found a mean 24.2% reduction in body weight at 48 weeks with retatrutide 12 mg, with no plateau reached by study end, and 83% of participants in that group achieving at least 15% body weight loss. For pharmacists, this breadth of evidence across T2D and obesity populations signals that retatrutide, if approved, could serve a wide range of patients already presenting at the pharmacy counter.^1,4

Safety, Tolerability, and Counseling Considerations

The most common adverse events in TRANSCEND-T2D-1 were nausea (up to 26.5%), diarrhea (up to 22.8%), and vomiting (up to 17.6%), occurring primarily during the dose escalation period and consistent with the tolerability profile of other incretin-based therapies. Pharmacists should be prepared to proactively counsel patients on the likelihood of transient gastrointestinal effects during titration and reinforce that these typically subside as the body adjusts to each dose level. Dysesthesia was reported in 2.3% to 4.5% of retatrutide-treated participants and was generally mild, with most cases resolving during treatment—another adverse effect for pharmacists to flag during patient education. Discontinuation rates due to adverse events were low, ranging from 2.2% to 5.1% across doses vs 0.0% with placebo.¹

What’s Next

Detailed TRANSCEND-T2D-1 results are expected to be presented at the American Diabetes Association Scientific Sessions in June and published in a peer-reviewed journal. The broader TRANSCEND-T2D phase 3 program—comprising more than 2050 participants across 3 global registrational trials—has additional readouts anticipated over the next year. As the data package grows, pharmacists will be well positioned to stay ahead of patient questions by tracking upcoming publications and monitoring for any regulatory submissions from Lilly.¹

REFERENCES

1. Lilly’s triple agonist, retatrutide, demonstrated significant reductions in A_1C and weight in first phase 3 trial for treatment of type 2 diabetes. News release. Eli Lilly and Company. March 19, 2026. Accessed March 25, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-demonstrated-significant

2. Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022;34(9):1234-1247.e9. doi:10.1016/j.cmet.2022.07.013

3. Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023;402(10401):529-544. doi:10.1016/S0140-6736(23)01053-X

4. Jastreboff AM, Kaplan LM, Frías JP, et al; Retatrutide Phase 2 Obesity Trial Investigators. Triple–hormone-receptor agonist retatrutide for obesity—a phase 2 trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972