The many TRIUMPHs of retatrutide

Posted in Diabetes, Obesity & Metabolism, Internal Medicine

October 10, 2026

10th October 2026, A/Prof Chee L Khoo

The topline results of TRANSCEND-T2D 1 were released in March 2026 and the full results have since been published. It was a trial involving patients with sub-optimally controlled T2D and obesity with the primary aim of better glycaemic control. The TRIUMPH series were designed to primarily demonstrate the efficacy of retatrutide in weight management in patients with obesity +/- T2D and a variety of clinical conditions (see Table 1). The primary endpoint for weight management is percent change in body weight, for obstructive sleep apnoea (OSA) is change in Apnoea‐Hypopnoea Index and for knee osteoarthritis (OA) includes change in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score. TRIUMPH-1 and TRIUMPH-2 have just published.

TRIUMPH trial series
Adapted from Giblin K. et al. (4)

Just a recap from March 2026, retatrutide is a once weekly triple hormone receptor agonist. It is a single molecule that can activate the receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. Retatrutide is a single molecule which has domains on the same molecule that that activate the GLP1, GIP and Glucagon receptors. The integration of glucagon-mediated energy expenditure with the appetite-suppressive and insulinotropic effects of GIP and GLP-1 agonism is hypothesised to explain the substantial weight loss and metabolic improvements observed in Phase 2 trials.

TRANSCEND-T2D 1 was a 40-week, phase 3, randomised, double-blind, placebo-controlled trial involving adults aged ≥18 years with type 2 diabetes (T2D) that is inadequately controlled by diet and exercise alone, HbA1c between 7·0% and 9·5% and BMI of at least 23 kg/m² (1). Participants were randomly assigned (1:1:1:1) to receive retatrutide (4 mg, 9 mg, or 12 mg) or placebo by once-weekly subcutaneous injection. The mean change from baseline in HbA_1c concentration was –1·69% (SE 0·11) with retatrutide 4 mg, –1·86% (0·10) with 9 mg, and –1·94% (0·08) with 12 mg, versus –0·81% (0·12) with placebo. The mean percentage change from baseline in bodyweight was –11·5% (SE 0·7) with retatrutide 4 mg, –13·9% (0·8) with 9 mg, and –15·3% (0·8) with 12 mg, versus –2·6% (0·5) with placebo. Remember, these are patients with T2D.

TRIUMPH-1 was a Phase 3 randomised controlled trial involving adults with obesity without diabetes to receive a once-weekly subcutaneous injection of retatrutide (at a dose of 4 mg, 9 mg, or 12 mg) or placebo for 80 weeks (2). There were 2339 participants who underwent randomisation. There was a subgroup of 574 participants with knee osteoarthritis and 243 participants with obstructive sleep apnoea. The primary outcomes were the percent change in body weight and the change in the WOMAC pain score (ranging from 1 to 10, with higher scores indicating worse pain) and the change in the apnea–hypopnoea index (AHI).

The mean percent change in body weight in the retatrutide groups was −17.6% (4-mg dose), −23.7% (9-mg dose), and −25.0% (12-mg dose) versus −3.9% in the placebo group. Among the participants with knee osteoarthritis, the corresponding changes in the pain score in the retatrutide groups for the hybrid estimand were −3.2, −3.5, and −3.6 versus −1.9 with placebo. Among the participants with obstructive sleep apnea, the corresponding changes in events per hour in the retatrutide groups for the hybrid-treatment estimand were −22.9, −34.3, and 31.7 versus −9.9. Note that the degree of weight loss in patients without diabetes in TRIUMPH-1 was significantly greater than that achieved in patients with diabetes in TRANSCEND-T2D 1.

TRIUMPH-2 was a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial involving adults (aged ≥18 years) with a BMI of 27 kg/m² or higher and type 2 diabetes (HbA_1c 6·5–10·5%) on stable treatment for T2D for at least 90 days before screening (diet or exercise alone, or up to three oral glucose-lowering medications), and a history of at least one self-reported unsuccessful dietary effort to reduce bodyweight (3). At baseline, the mean BMI was 38·2 kg/m², mean HbA_1c was 7·71%, median duration of obesity was 21 years, and median duration of diabetes was 5·6 years (2·6–10·4). The mean percentage change from baseline in bodyweight at week 80 was −11·9% (SE 0·6) with retatrutide 4 mg, −16·8% (0·7) with retatrutide 9 mg, −18·8% (0·7) with retatrutide 12 mg, and −5·1% (0·7) with placebo. Once again, patients with T2D have lesser weight loss.

We can see that the triple hormone receptor agonist, retatrutide is definitely efficacious in HbA1c reduction and weight management in patients with or without T2D. There are also improvements in knee osteoarthritis pain and AHI scores in those patients with knee osteoarthritis and OSA respectively. The data is out and it is a matter time before it is approved by the FDA and then TGA. It will be sooner than you think. There are more TRIUMPH data to be published.

References:

1. Bajaj HS, Welch M, Shah P, Luna E, Jaouimaa FZ, Liu B, Liu R, Chen Y, Patel H, Bartee A. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. Lancet. 2026 Jun 13;407(10546):2402-2413.

2. Jastreboff AM, Kaplan LM, Davies MJ, Wilding JPH, Ahmad NN, Murray M, Du Y, Makarova N, Giblin K, Schloot NC, Wang Y; TRIUMPH-1 Investigators. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity. N Engl J Med. 2026 Sep 29
3. Bellido V, le Roux CW, Ekinci EI, Bjornstad P, Frias JP, Giblin K, Eyde S, Park SY, Ferro J, Johnson C, Taylor A. Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2): a double-blind, parallel-group, randomised, placebo-controlled, phase 3 trial. Lancet. 2026 Oct 10;408(10563):1455-1472.
4. Giblin K, Kaplan LM, Somers VK, Le Roux CW, Hunter DJ, Wu Q, Lalonde A, Ahmad N, Bethel MA. Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials. Diabetes Obes Metab. 2026 Jan;28(1):83-93.