medwireNews: People with type 2 diabetes treated with the single peptide triple agonist retatrutide achieve clinically meaningful improvements in glycemic control and reductions in bodyweight, suggests a phase 2 study published in The Lancet.
The findings, which were simultaneously presented at the 83rd ADA Scientific Sessions in San Diego, California, USA, confirm those of the 12-week phase 1 study and “support phase 3 clinical development” of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide (GLP)-1, and glucagon receptor agonist, the researchers comment.
The double-blind trial involved 281 participants, with a mean age of 56.2 years, from 42 centers in the USA. Of these, 56% were women and 84% were White.
The participants were randomly assigned to receive once-weekly injections of placebo, dulaglutide 1.5 mg, or one of four retatrutide maintenance doses of 0.5 mg, 4.0 mg (either with or without escalation from a starting dose of 2.0 mg), 8.0 mg (with slow dose escalation from 2.0 mg to 4.0 mg or fast escalation from a starting dose of 4.0 mg), or 12.0 mg (with slow dose escalation from a starting dose of 2.0 mg).
Tamer Coskun (Eli Lilly and Company, Indianapolis, Indiana, USA) and co-researchers highlight the inherent strength of their study design for “testing multiple titration regimens and different starting doses to assess safety and tolerability to help inform dose selection for the phase 3 clinical programme.”
The primary endpoint – change in glycated hemoglobin (HbA1c) at 24 weeks – showed significant decreases from a mean of about 8.3% (66.9 mmol/mol) at baseline in all retatrutide treatment groups. The largest reduction of 2.02% (22.07 mmol/mol) was seen in the 12 mg treatment group, report the researchers.
“Decreases were robust with doses of 4 mg and higher and showed dose dependency up to 8 mg, with smaller differences between the 8 mg and 12 mg groups, suggesting a maximal effect or perhaps requiring more time on treatment to further differentiate at higher doses,” they point out.
Coskun and team add that HbA1c reductions with retatrutide were significantly greater than with placebo (0.01%; 0.12 mmol/mol) for all but the lowest 0.5 mg dose, and significantly greater than with dulaglutide (1.41%; 15.40 mmol/mol) at the 8.0 mg slow escalation and 12.0 mg doses.
In addition, they report that significantly more people treated with retatrutide at doses of 4.0 mg and above achieved an HbA1c of 7.0% or less at 24 weeks than did those treated with placebo, at an average of 53–86% versus 22%. And a significant difference versus dulaglutide (60%) was seen with the 8.0 mg slow escalation and 12.0 mg doses.
The improved glucose control with retatrutide was maintained at 36 weeks, with HbA1c reductions of up to 2.16% (23.59 mmol/mol) in the 12.0 mg treatment group. At this point, there was also “robust bodyweight reduction” with the treatment,” note the investigators.
There were dose-dependent weight reductions of up to 16.94% with retatrutide 12.0 mg at 36 weeks, from an average at baseline of 98.2 kg, with significant differences compared with placebo (3.00%) and dulaglutide (2.02%) for doses of 4.0 mg and above.
The researchers note that “participants were still losing weight” at time of reporting and highlight that “[t]his magnitude of bodyweight reduction has not been reported so far in any other phase 2 or 3 trials testing weekly GLP-1 or GIP and GLP-1 receptor agonists in people with type 2 diabetes.”
They also report that retatrutide at the higher doses was associated with superior improvements from baseline, compared with placebo and dulaglutide, in fasting serum glucose, insulin sensitivity, and glucagon, as well as systolic and diastolic blood pressure and levels of non-high-density lipoprotein, cholesterol, and triglyceride.
The most common treatment-emergent adverse events associated with retatrutide were mild-to-moderate nausea, diarrhoea, vomiting, and constipation, occurring in 13–50% of patients versus 13% and 35% of those in the placebo and dulaglutide groups, respectively. Thus, demonstrating a safety profile “consistent with that of tirzepatide and GLP-1 receptor agonists,” the team points out.
Discussing the findings in a related comment, Stephen Bain and Thinza Min, both from Swansea University Medical School in the UK, highlight that the “glucose-lowering effect of retatrutide is certainly substantial,” and while the weight reduction of more than 16% is “impressive,” they note that the active comparator dulaglutide at 1.5 mg “is not renowned for weight loss.”
They conclude: “Going forward, a phase 3 clinical trial programme of retatrutide to include comparisons with higher dose GLP-1 receptor agonists and dual incretin agonists is needed.”
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Lancet 2023; doi:10.1016/S0140-6736(23)01053-X
Lancet 2023; doi:10.1016/S0140-6736(23)01182-0