Lilly’s triple agonist retatrutide shows broad and substantial benefits across weight, blood sugar, knee pain and sleep apnea in Phase III trials

Eli Lilly has recently reported further positive outcomes from pivotal Phase 3 trials of retatrutide, an investigational first-in-class GIP, GLP-1, and glucagon triple hormone receptor agonist. The data point to substantial weight loss alongside meaningful gains across a cluster of obesity-related conditions, namely knee osteoarthritis pain, moderate-to-severe obstructive sleep apnea, and type 2 diabetes.

“Obesity drives more than 200 downstream diseases, yet we have historically treated those conditions one at a time and in silos,” said Ania Jastreboff, M.D., Ph.D., Professor of Medicine and Pediatrics (Endocrinology) at the Yale School of Medicine, Director of the Yale Obesity Research Center (Y-Weight), and lead investigator. “In TRIUMPH-1 and TRANSCEND-T2D-1, treatment with retatrutide resulted in substantial weight reduction together with clinically meaningful improvements in glycemia, knee osteoarthritis pain, and obstructive sleep apnea, with many individuals reaching what are classified as healthy-range weight and normal blood sugar levels. These findings demonstrate what may be possible when we treat obesity and impact overall health, and what this could mean for people living with obesity and its related complications.”

TRIUMPH-1 was structured around an overarching obesity trial for adults, with two nested basket trials sitting within it, one focused on knee osteoarthritis pain and one on moderate-to-severe obstructive sleep apnea. Retatrutide cleared the primary endpoints across all three at 80 weeks. Those on retatrutide 9 mg lost an average of 64.4 lbs (25.9%) and those on 12 mg lost 70.3 lbs (28.3%), while even participants on the 4 mg dose, reached via a single escalation step, shed an average of 47.2 lbs (19.0%). Nearly two thirds of those on the 12 mg dose (65.3%) dropped below a BMI of 30, with a further 33.3% reaching a BMI below 25, which falls within the healthy range. A prespecified extension among participants with a baseline BMI of 35 or above showed those continuing on 12 mg through 104 weeks lost an average of 85.0 lbs (30.3%). On the complication side, WOMAC pain subscale scores fell by up to 4.3 points (73.1%) from a baseline of 6.0 in those with knee osteoarthritis, and the apnea-hypopnea index dropped by up to 36.1 events per hour (60.6%) from a baseline of 58.6 in those with moderate-to-severe obstructive sleep apnea.

“Across TRIUMPH-1 and TRANSCEND-T2D-1, retatrutide delivered substantial weight loss, meaningful A1C reduction, and improvements in knee osteoarthritis pain and moderate-to-severe obstructive sleep apnea, a breadth and magnitude of outcomes that’s striking to see with a single therapy,” said Kenneth Custer, Ph.D., Executive Vice President and President, Lilly Cardiometabolic Health. “By addressing weight, glycemia and obesity-related complications together, these results highlight retatrutide’s potential across the cardiometabolic spectrum and reinforce our commitment to delivering options that meet patients’ needs and preferences.”

In TRANSCEND-T2D-1, retatrutide cleared both its primary and all key secondary endpoints at 40 weeks in adults with type 2 diabetes, combining strong A1C reductions with substantial weight loss. Working from an average baseline A1C of 7.9%, participants achieved average reductions of up to 2.0%. Nine in ten of those on retatrutide brought their A1C below 7.0%, the general target set by the American Diabetes Association for type 2 diabetes management, while 85% reached 6.5% or below, a more ambitious threshold suited to those earlier in their disease course. Nearly half (46%) attained an A1C below 5.7%, the marker for normoglycemia. Those on the 12 mg dose also lost an average of 36.6 lbs (16.8%), with weight loss showing no signs of levelling off at the 40-week mark.

Both trials also recorded meaningful improvements from baseline across a range of cardiovascular risk markers. In TRIUMPH-1 at 80 weeks, retatrutide brought triglycerides down by up to 41.0%, non-HDL cholesterol by 24.2%, systolic blood pressure by 12.3 mmHg, and waist circumference by 9.5 inches (24.1 cm). In TRANSCEND-T2D-1 at 40 weeks, corresponding reductions reached up to 39.6% for triglycerides, 19.8% for non-HDL cholesterol, 6.4 mmHg for systolic blood pressure, and 4.9 inches (12.4 cm) for waist circumference.

---

---

Related Topics and Keywords

elli lilly, Lilly's, Lilly's triple agonist retatrutide, Phase III trials, retatrutide, sleep apnea