Phase 2 Type 2 Diabetes Trial of Retatrutide (NCT04867785)

Study Overview

The Phase 2 type 2 diabetes trial of retatrutide, registered as NCT04867785, was a pivotal study that established the drug’s glycemic efficacy in patients with type 2 diabetes. Published online by Rosenstock et al. in The Lancet on June 26, 2023, and presented at the American Diabetes Association Scientific Sessions that month, the trial showed dose-dependent reductions in HbA1c. The study also included a dulaglutide active comparator arm, providing valuable context for the results.

Study Design

Design

Randomized, double-blind, placebo-controlled and active-comparator-controlled, dose-ranging, parallel-group study.

Duration

36 weeks of treatment.

Population

Adults aged 18-75 years with:

• Type 2 diabetes
• HbA1c 7.0-10.5% at screening
• Treated with diet and exercise alone, or with a stable dose of metformin (at least 1,000 mg a day), for at least 3 months before screening
• BMI 25-50 kg/m2

Treatment Arms

Participants were randomized in a 2:2:2:1:1:1:1:2 ratio to one of eight arms:

1. Placebo
2. Dulaglutide 1.5 mg (active comparator, once weekly)
3. Retatrutide 0.5 mg
4. Retatrutide 4 mg, starting at 2 mg
5. Retatrutide 4 mg, no escalation
6. Retatrutide 8 mg, starting at 2 mg (slow escalation)
7. Retatrutide 8 mg, starting at 4 mg (fast escalation)
8. Retatrutide 12 mg, starting at 2 mg

The inclusion of dulaglutide 1.5 mg as an active comparator was a strength of the study design, allowing comparison with an established GLP-1 receptor agonist.

Endpoints

Primary endpoint: Change in HbA1c from baseline at 24 weeks.

Key secondary endpoints:

• Change in HbA1c at 36 weeks
• Proportion reaching HbA1c targets
• Change in fasting plasma glucose
• Percent change in body weight
• Changes in cardiometabolic parameters

Results

Glycemic Control

HbA1c change at 24 weeks, the primary endpoint (mean baseline about 8.3%):

All retatrutide groups except 0.5 mg lowered HbA1c significantly more than placebo. Only the 8 mg (2 mg start) and 12 mg groups lowered it significantly more than dulaglutide 1.5 mg. The 4 mg groups were close to dulaglutide. Results were consistent at 36 weeks, when the 12 mg group’s reduction was 2.16 points.

At 24 weeks, 53-86% of participants on 4 mg or more reached an HbA1c of 7.0% or less, against 22% on placebo.

Near-Normoglycemia

We have not been able to confirm how many participants reached an HbA1c below 5.7% (the non-diabetic range), so no figure is given here.

Weight Loss

Despite the shorter treatment duration (36 weeks vs. 48 weeks in the obesity trial) and the type 2 diabetes population (which typically experiences less weight loss with incretin-based therapies than non-diabetic individuals), significant weight reductions were observed:

The weight loss achieved in the type 2 diabetes population, while somewhat lower than in the non-diabetic obesity trial (likely due to the shorter duration and the known attenuating effect of diabetes on incretin-mediated weight loss), was nevertheless substantial and exceeded that of dulaglutide and most other diabetes treatments.

Fasting Plasma Glucose

Fasting glucose fell more with the higher retatrutide doses than with placebo or dulaglutide.

Safety

The safety profile in the type 2 diabetes population was consistent with observations from the obesity trial:

Most common adverse events: Mild-to-moderate gastrointestinal events (nausea, diarrhea, vomiting and constipation) were reported in 35% of participants on retatrutide overall. The rate ranged from 13% in the 0.5 mg group to 50% in the 8 mg fast-escalation group, against 13% on placebo and 35% on dulaglutide 1.5 mg (Rosenstock et al., The Lancet 2023, abstract). Rates for each symptom by dose are not given in the abstract.

Hypoglycemia: No severe hypoglycemia was reported. Participants were on diet and exercise alone or metformin, not sulfonylureas or insulin, which usually cause low blood sugar alongside GLP-1 drugs.

Treatment completion: Of 281 participants, 237 (84%) completed the study and 222 (79%) completed study treatment. The abstract does not give a separate rate of stopping because of adverse events. No severe hypoglycemia and no deaths were reported.

Significance

Superior to Active Comparator

Including dulaglutide 1.5 mg as an active comparator showed that retatrutide at higher doses gives much larger blood sugar and weight benefits than an established GLP-1 receptor agonist. The comparison was not against the highest available dose of a GLP-1 agonist, but it still gives useful clinical context.

Diabetes Remission Potential

The trial did not report diabetes remission. Large HbA1c reductions while on treatment are not the same as remission, which is usually defined as normal HbA1c without diabetes medicines.

Metabolic Breadth

Beyond glucose and weight, improvements in multiple cardiometabolic parameters were observed, supporting the idea that triple agonism brings broad metabolic benefits in people with type 2 diabetes.

Publication

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. The Lancet. 2023;402(10401):529-544. Published online June 26, 2023. doi:10.1016/S0140-6736(23)01053-X

Limitations

• 36-week treatment duration; longer treatment may produce additional glycemic and weight benefits
• Conducted entirely at U.S. sites with limited ethnic/racial diversity
• Active comparator was dulaglutide 1.5 mg (not the most potent available GLP-1 agonist dose)
• Participants were on diet and exercise alone or metformin; results may differ in other treatment settings
• Small sample size limits safety signal detection