Directory Image
This website uses cookies to improve user experience. By using our website you consent to all cookies in accordance with our Privacy Policy.

New weight loss drug —a novel triple agonist: from discovery to clinical proof of concept

Author: Jerry Carter
by Jerry Carter
Posted: Sep 19, 2022

Bariatric surgery remains the most effective treatment for severely obese patients, but is not the first-line treatment of choice due to the risks associated with surgery. Glucagon may be a target as some studies have shown that it exhibits reduced body weight and appetite, delays gastrointestinal transit and stimulates insulin secretion under hyperglycemic conditions. In addition, glucose-dependent insulinotropic polypeptide (GIP), an entero-insulinotropic hormone, is able to regulate glucagon secretion in a glucose-dependent manner, promote postprandial lipid clearance, and regulate food intake.

Dually active single-molecule agonist peptides targeting the GIP receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), and glucagon receptor (GCGR) have been tested in the clinic and have been shown to have greater weight loss capacity than single agonists. So does direct simultaneous targeting of these three receptors provide better efficacy?

Recently, Tamer Coskun's team from Lilly Corporate Center in Indianapolis, published an article in Cell Metabolism entitled "LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept". They demonstrate that LY3437943 is a triple glucagon, GIP, and GLP-1 receptor agonist for the treatment of obesity and type 2 diabetes that reduces body weight by increasing energy expenditure and reducing calorie intake in obese mice, and that the safety and tolerability of LY3437943 in healthy subjects is similar to that of other entero-insulin-based therapies.

LY is a 39 amino acid single peptide designed from the GIP peptide backbone to achieve triple agonist activity on GCGR, GIPR, and GLP-1R. To assess the intrinsic potency of LY, the authors used HEK-293 expressing human GCGR, GIPR, or GLP-1R, respectively, to measure the accumulation of 3',5'-cyclic adenosine monophosphate (cAMP) as a second messenger downstream of receptor activation. Despite the different potencies, LY was effective in activating all three receptors, and this triple activation potency was similarly exerted in transgenic mice.

To investigate the effects on body weight, energy metabolism, body composition, and hepatic steatosis, the authors administered LY to C57/Bl6 diet-induced obese (DIO) mice. Results showed that LY dose-dependently reduced body weight (mainly due to reduced fat mass) and calorie intake. In addition, LY reduced blood glucose and plasma insulin, alanine aminotransferase and hepatic triglycerides, indicating improved insulin sensitivity and liver health. In terms of weight loss, the authors compared the LY group with a calorie intake matched group, resulting in a 35% weight loss within the first 10 days of the treatment period, while CIM resulted in a 20% weight loss. However, the reduction in calorie intake in the CIM group was accompanied by a significant reduction in energy expenditure. As the initial suppressive treatment effect on calorie intake waned, the CIM group gradually gained weight and recovered slowly after a decrease in energy expenditure. In contrast, mice treated with LY continued to maintain their initial weight loss and increased energy expenditure due to maintenance of pre-treatment energy expenditure levels, resulting in a significant negative energy balance and lipid oxidation. In addition, targeted metabolomics results showed that LY caused significant changes in 50% of the 161 metabolic species measured that are associated with energy metabolic pathways.

After evaluating the cardiovascular safety of LY using crab-eating monkeys, the authors conducted the first human phase I study of LY in a single incremental dose. A total of 47 healthy participants were enrolled in this study, 45 of whom received at least 1 dose of LY or placebo, while 2 discontinued prior to the first randomized treatment.

In conclusion, this work demonstrates that LY3437943 is a novel triple agonist peptide acting on GCGR, GIPR, and GLP-1R. It reduces body weight and improves glycemic control, causes increased energy consumption and shows a similar safety and tolerability profile to other entero-insulins.

About the Author

A fan of biotechnology who likes to post articles in relevant fields regularly

Rate this Article
Leave a Comment
Author Thumbnail
I Agree:
Author: Jerry Carter
Professional Member

Jerry Carter

Member since: Jan 15, 2020
Published articles: 201

Related Articles