A New Medication Targeting Three Hormones


Session: Retatrutide (LY3437943), a Novel GIP/GLP-1/Glucagon Receptor Triagonist—Obesity, NAFLD, and T2D Phase 2 Trial Results 

Speakers at this ADA Scientific Sessions presentation included: Lee Kaplan, MD, Ph.D. (The Obesity and Metabolism Institute), Matthias Tschöp, MD (Helmholtz Zentrum München), David D’Alessio, MD (Duke Division of Endocrinology), Arjun J. Sanyal, MD (Virginia Commonwealth University), Julio Rosenstock, MD (Director of the Dallas Diabetes Research Center at Medical City and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center) and Ania M. Jastreboff, MD, Ph.D. (Associate Professor, Yale University). 

This panel of experts presented exciting research for a new medication that could be used for diabetes management. Here’s what you need to know about Retatrutide now, so you can talk to your providers if it becomes available!

Retatrutide, the new kid on the block

Retatrutide is an experimental, once-weekly injectable medication that is currently in phase 2 of clinical trials

It is a single peptide that targets the receptor of three hormones: glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). It is not yet approved by the Food and Drug Administration (FDA). 

Unlike other GIP/GLP-1 receptor agonist medications like Mounjaro or GLP-1 receptor agonist medications like Ozempic—this medication is the first of its kind to also target glucagon. 

Leveraging the use of three hormones 

Dr. D’Alessio discussed that utilizing GIP, GLP-1 and glucagon receptor triagonists together has impactful benefits for people with type 2 diabetes (T2D)

Targeting glucagon does not only impact blood sugar levels. A chronic infusion of glucagon can also result in suppressed appetite. Activating glucagon might have beneficial effects on energy balance (satiety and weight maintenance). 

Dr. D’Alessio suggests that contrary to popular belief, giving a glucagon agonist to patients has the potential to greatly improve health. High levels of glucagon enhance insulin secretion and decreases how fast the body uses up that insulin. Adding glucagon to a GLP-1 can help by: 

  • Causing more energy to be used (calories)
  • Not resulting in higher blood sugars
  • Improving weight loss and suppressing appetite
  • Improving lipids, triglycerides and cholesterol levels
  • Improving liver health 

Phase 2 trial efficacy and safety results 

The phase 2 trial consisted of 338 participants, all adults from ages 18-75 with either a body mass index (BMI) over 35, or over 27 with another chronic health condition—hypertension or type 2 diabetes.

The phase 2 study looked at the differences between weekly injections of retatrutide versus a placebo over a 48-week trial. Doses of retatrutide were evaluated at 1 mg, 4 mg, 8 mg, and 12 mg. 

Effects on obesity 

Dr. Jastreboff shared that participants in the study saw remarkable results in weight loss. At 24 weeks (halfway through the study), participants lost an average of 17.9% of their body weight on 12mg of retatrutide weekly. 

At 48 weeks, participants on the weekly 12mg dose lost an average of 24.2% of their total body weight. This means that the average participant on the highest dose of the medication lost about a quarter of their body weight at 11 months. 

The average weight loss was 58 pounds, and weight loss continued even after the study ended and the medication stopped. 100% of study participants lost at least 5% of their body weight on the 8 mg and 12mg retatrutide doses. Women on average lost more weight than men. 

These initial results show that this is a more powerful medication than anything currently on the market for weight loss. Given that people living with T2D are constantly told to “just lose weight” but are never given support or the tools needed to help achieve any weight loss goals, retatrutide has the potential to help many people.

Effects on NAFLD

Dr. Sanyal showed that non-alcoholic liver fat was lowered on all doses of the retatrutide versus the placebo. 

80% or more of participants on both the 8mg and 12 mg doses had a greater than 70% relative reduction in liver fat. The impacts of retatrutide on NAFLD proved to be dose-dependent, with 86% of participants on the 12 mg weekly dose resolving their hepatic steatosis at week 48. 

Additionally, the medication improved lipid and blood pressure levels at 48 weeks. 

Effects on T2D management 

People with obesity and diabetes typically have a harder time losing weight than people with obesity and no diabetes. However, in the study, retatrutide helped improve both blood sugars levels and resulted in significant weight loss. 

Dr. Rosenstock showed the following improvements in blood sugar levels were seen:

  • Average A1C at baseline was 8.3% and was reduced to 6.1% with the 12 mg dose at 36 weeks.
  • The average A1C reduction was 0.45%, with 76% of participants achieving better A1C outcomes.
  • A1C of <6.5% was achieved in up to 82% of study participants. 
  • A1C of <5.7% was achieved in up to 31% of study participants.

Adverse side effects 

As with many medication, even retatrutide showed some not-so-great side effects. Between 73-90% of the study participants experienced adverse side effects, including gastrointestinal issues, nausea, vomiting, diarrhea, constipation, fatigue, early satiety and decreased appetite. 

However, the side effects were largely mild to moderate, and went away over the duration of study. TRIUMPH phase 3 trials are now underway with the hope of FDA approval soon. 

These are exciting study results that have the potential to radically change the health outcomes of people who live with NAFLD, obesity and type 2 diabetes. At Beyond Type 2, we’re committed to following these advancements to keep the community informed, so make sure to sign up for our newsletter and follow our news coverage for retatrutide updates!

WRITTEN BY Beyond Type 2 Editorial Team, POSTED 06/27/23, UPDATED 06/27/23

This piece was authored collaboratively by the Beyond Type 2 Editorial Team.