‘Bariatric Surgery-Level’ Weight Loss With Novel Triple-Agonist

NEW ORLEANS — Participants with obesity achieved weight loss on par with bariatric surgery and had improvements in two obesity-related conditions while taking a once-weekly investigational triple hormone receptor agonist, the phase III TRIUMPH-1 study showed.

In 2,339 adults, mean change in body weight by week 80 was -19% with retatrutide 4 mg, -25.9% with 9 mg, and -28.3% with 12 mg, compared with -2.2% with placebo when paired with lifestyle counseling (P<0.001 for all groups vs placebo).

This translated to an average weight loss of up to 70.3 lbs (31.9 kg) with the highest dose, Ania Jastreboff, MD, PhD, of Yale University School of Medicine in New Haven, Connecticut said at the American Diabetes Association (ADA) Scientific Sessions. Weight loss was 30.3% with 12 mg, or 85 lbs (38.5 kg) at the end of a 24-week extension phase that involved a subset of participants.

“These are bariatric-surgery levels of weight reduction,” Jastreboff said during a press conference.

Impacts on osteoarthritis and obstructive sleep apnea (OSA) were also primary endpoints.

In 574 participants with knee osteoarthritis, reductions in WOMAC pain subscale score ranged from 3.66 to 4.30 points with retatrutide versus 2.24 points with placebo (P<0.001 for all). Score reductions with the two highest retatrutide doses surpassed the clinically significant threshold of 4 points, translating to a roughly 70% decrease in pain.

For the 243 participants with OSA, reductions in the Apnea-Hypopnea index (AHI) ranged from 25.7 to 36.1 events/hour versus 11.1 events/hour with placebo (P<0.01). This surpassed the clinically significant threshold of 15 events/hour, translating to more than a 60% decrease in AHI.

TRIUMPH-1 was a double-blind trial that randomized participants 1:1:1:1 across the three retatrutide dosages and placebo. At baseline, mean body weight was 248.5 lbs, body mass index (BMI) was 40, and waist-to-height ratio was 0.7. The WOMAC pain subscale score was 6 and the AHI was 58.6 events/hour.

After screening, participants entered a 16-week dose-escalation phase in which all retatrutide-treated participants started on 2 mg, followed by an 80-week treatment period. The 4-mg group had only one up-titration step.

Nearly half of the participants on the highest retatrutide dose lost at least 30% of their body weight, and over one in four lost at least 35%. Roughly two-thirds of those on 12 mg achieved a BMI under 30 — the threshold for obesity — while a third achieved a BMI under 25, the threshold for normal weight.

This magnitude of weight loss allows for a shift toward a “treat-to-target approach” rather than a change-in-weight approach, Jastreboff noted.

“If we think about other diseases — say type 2 diabetes — there’s a [HbA1c] target. When we think about obesity, we really haven’t had targets. We have relative weight reduction thresholds. We don’t say, ‘Oh, we’re going to decrease someone’s blood pressure by 10%, we say the goal is less than 120/80,” she explained to MedPage Today. “In obesity, the question is, can we move towards targets. Now, those targets will likely not only be anthropometric, not only be BMI, or waist-to-height. We have to also show that those types of targets then translate to health outcomes.”

“Until we had agents that were enabling us to reach towards targets, we had to use relative change, that’s why the initial threshold was losing ≥5% of body weight. As the molecules became more powerful, we were able to start thinking about targets,” she noted.

More than a quarter of participants achieved a waist-to-height ratio under 0.5 on the highest dose. Females lost more weight on average than men while on treatment by week 80 (-30.8% vs -23.2% with 12 mg).

Cardiometabolic measures also improved with retatrutide. Compared with placebo, participants on the highest dose had significantly greater reductions in systolic blood pressure (-12.3 mmHg vs -1.1 mmHg), triglycerides (-41% vs -5%), LDL cholesterol (-19.6% vs -2.1%), and high-sensitivity C-reactive protein (-63.8% vs -23.5%). Nearly all with prediabetes reverted to normoglycemia (95.7%).

More participants on active treatment experienced at least one serious adverse event (7.7%-10.5% vs 5.5% with placebo). Six deaths occurred during the study — four in the retatrutide groups and two in the placebo group.

Gastrointestinal adverse events were common with retatrutide and increased with the dose. These included nausea (28.6-42.4% vs 14.8% with placebo), diarrhea (25.2-34.1% vs 13.5%), constipation (23.8-26.1% vs 10.9%), and vomiting (10.6-25.3% vs 4.8%). Gastrointestinal events were the most common reason for treatment discontinuation (2.2-4.6% vs 1.2%).

Urinary tract infection emerged as a new safety signal (6.8-8.1% vs 4.8%). Most were mild to moderate and resolved with treatment, and nearly all occurred in women. This could be related to hydration or increased sexual activity, Jastreboff suggested. Reported hypotension was also more common with retatrutide, especially in those taking antihypertensive medications.

The drug’s effects on muscle and bone are not yet known.

Future installments of the TRIUMPH clinical program will report on cardiovascular and renal risk reductions, liver outcomes, and chronic low back pain in individuals with obesity.