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 by Rosenstock et al. in The Lancet in June 2023, the trial demonstrated that retatrutide produced potent, dose-dependent reductions in HbA1c, with a majority of participants at higher doses achieving non-diabetic glycemic levels. 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
• Stable metformin therapy (≥1500 mg/day or maximum tolerated dose) for at least 3 months
• BMI 25-50 kg/m2

Treatment Arms

Participants were randomized to one of six arms:

1. Placebo
2. Dulaglutide 1.5 mg (active comparator, once weekly)
3. Retatrutide 0.5 mg (fixed dose)
4. Retatrutide 4 mg (escalating)
5. Retatrutide 8 mg (escalating)
6. Retatrutide 12 mg (escalating)

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 achieving HbA1c <7.0% and <5.7%
• Change in fasting plasma glucose
• Percent change in body weight
• Changes in cardiometabolic parameters

Results

Glycemic Control

HbA1c reductions at 36 weeks (mean baseline ~8.3%):

The 8 mg and 12 mg retatrutide groups demonstrated statistically significantly greater HbA1c reductions than both placebo and dulaglutide 1.5 mg. The 4 mg retatrutide group achieved HbA1c reductions comparable to dulaglutide 1.5 mg.

Near-Normoglycemia

One of the most noteworthy findings was the high proportion of participants achieving HbA1c below 5.7% (the normal, non-diabetic range). In the 12 mg group, approximately 62% of participants reached this threshold, suggesting that retatrutide can produce near-complete normalization of glycemic control in a substantial proportion of patients with type 2 diabetes.

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 reductions were dose-dependent and robust:

• 12 mg group: ~-55 mg/dL reduction (from baseline of ~170 mg/dL)
• 8 mg group: ~-47 mg/dL reduction
• 4 mg group: ~-32 mg/dL reduction

Safety

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

Most common adverse events (across active treatment arms):

• Nausea: ~12-24% (dose-dependent)
• Diarrhea: ~10-18%
• Vomiting: ~6-13%
• Decreased appetite: ~8-16%
• Constipation: ~5-10%

Hypoglycemia: The rate of clinically significant hypoglycemia was low across all groups. Hypoglycemia events were primarily associated with concomitant sulfonylurea use, consistent with the glucose-dependent mechanism of retatrutide’s insulin-promoting effects.

Treatment discontinuation due to AEs: Ranged from approximately 6% to 14% across active treatment groups, with higher rates at higher doses. These rates are within the range observed for other incretin-based therapies in type 2 diabetes populations.

Significance

Superior to Active Comparator

The inclusion of dulaglutide 1.5 mg as an active comparator demonstrated that retatrutide at higher doses provides glycemic and weight benefits substantially exceeding those of an established GLP-1 receptor agonist. This comparison, while not against the highest available dose of a GLP-1 agonist, provides meaningful clinical context.

Diabetes Remission Potential

The observation that a majority of participants in the 12 mg group achieved HbA1c below 5.7% raises the possibility of pharmacologically induced diabetes remission. While the durability of this effect and its clinical implications require further study, it represents a striking finding.

Metabolic Breadth

Beyond glucose and weight, improvements in multiple cardiometabolic parameters were observed, supporting the concept that triple agonism produces comprehensive metabolic benefits in the type 2 diabetes population.

Publication

Rosenstock J, Frias JP, 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-comparator controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet. 2023;402:529-544. 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 background metformin; results may differ in other treatment settings
• Small sample size limits safety signal detection