Novel Triple-Hormone Agonist Boosts Beta-Cell Function in T2D

ORLANDO — An investigational triple-hormone receptor agonist improved metabolic profiles of people with obesity with or without type 2 diabetes, an exploratory biomarker analysis of a phase II trial found.

After 36 weeks of treatment with retatrutide, people with type 2 diabetes on most doses had significantly larger improvements in fasting glucose than placebo or dulaglutide (Trulicity), reported Melissa K. Thomas, MD, PhD, of Eli Lilly & Company, at the American Diabetes Association (ADA) annual meeting.

People on the highest dose had the largest drops in fasting glucose:

• -17.5 mg/dL for 0.5 mg
• -17.3 for placebo
• -27.5 for dulaglutide 1.5 mg
• -30.1 for 4 mg
• -55.2 for 8 mg
• -67.8 for 12 mg

A similar pattern was reported for fasting insulin changes, with the two highest retatrutide doses yielding the largest reductions:

• +35.7 mU/L for dulaglutide
• +5 for 0.5 mg
• -11.6 for 4 mg
• -22.2 for placebo
• -36.3 for 12 mg
• -39.3 for 8 mg

“Many people living with type 2 diabetes are taking multiple medications to try to reach their treatment goals,” Thomas said during an ADA presentation. “New medications that can simplify treatment regimens and help them reach their goals for treatment are needed.”

These two metabolic markers also significantly improved with retatrutide in people with overweight or obesity but were free of diabetes. The largest reductions corresponded with the highest dose (12 mg) at week 48: -10.6 mg/dL for fasting glucose and -58.3 mU/L for fasting insulin.

“We wanted in this analysis to use exploratory biomarkers that were within both phase II trial protocols to better understand how the beta cells might work and how insulin action was occurring in the context of these trials,” Thomas explained.

Findings from the phase II trial program were presented at the 2023 ADA meeting, which reported the largest weight loss yet in an obesity trial. The once-weekly triple-agent acts as an agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors.

The type 2 diabetes trial included 281 participants with an average age of 56, baseline body weight of 98.2 kg, and BMI of 35. HbA1c was 8.3%, fasting insulin was 16.6 mU/L, and fasting glucose was 170.5 mg/dL. Prior to study entry, they were being treated with diet and exercise alone or with a stable dose of metformin.

As for the obesity trial, the 338 participants were free of type 1 and type 2 diabetes at baseline. The average age was 48.2, baseline body weight was 107.7 kg, and average BMI was 37.3. HbA1c was 5.5%, fasting insulin was 186 mU/L, and fasting glucose was 93.8 mg/dL.

In the trial, participants with obesity free of diabetes on the highest dose (12 mg) lost 17.5% of their body weight by week 24 and went on to lose 24.2% by week 48.

As for people with type 2 diabetes on the highest dose, there was a 2.02% greater HbA1c reduction compared with dulaglutide by week 24, maintained through to the end of the trial at 36 weeks. This patient population also had significant weight loss, averaging a 16.94% reduction.

All trial participants also received lifestyle intervention but weren’t required to stick to a caloric deficit.

Adiponectin — a marker of insulin sensitivity — also significantly increased with retatrutide in both patient populations:

• With type 2 diabetes at week 36: +51.5 mg/L with 8 mg; +41.1 mg/L with 12 mg
• With obesity at week 48: +70.2 mg/L with 8 mg; +57.2 mg/L with 12 mg

Thomas pointed out that as adiponectin levels increase, they’re associated with better efficiency of insulin to lower glucose levels.

HOMA2-IR indices, which act as a measure of insulin resistance, also decreased in both patient populations. The 12-mg dose yielded the largest reductions (-38.7% in type 2 diabetes at 36 weeks; -52% in obesity at 48 weeks).

HOMA2-B index — a marker of beta-cell function in diabetes — also rapidly increased with retatrutide by 87.8% in people with type 2 diabetes at the highest dose. This marker didn’t significantly change in people with obesity without diabetes. “There wasn’t a metabolic need to increase insulin secretion [in those without diabetes],” said Thomas.

Similarly, proinsulin and proinsulin/C-peptide ratios — measures of beta-cell stress and dysfunction — dropped with retatrutide by up to 70.5% and 61.6%, respectively, in the type 2 diabetes population. While proinsulin levels also significantly dropped in people with obesity without type 2 diabetes, the proinsulin/C-peptide ratios didn’t significantly change.

“We continue to be encouraged about the clinical development program for retatrutide,” Thomas added. “We have ongoing clinical trials in phase III to further investigate the safety and efficacy of the molecule.”

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