New Drug Targets Four Hormones for Enhanced Weight Loss

Researchers Aim to Surpass Bariatric Surgery Results

A team of scientists is developing a novel compound that simultaneously impacts four key hormones regulating appetite and metabolism, potentially offering a more effective and tolerable approach to weight management than current medications. This research seeks to address limitations of existing drugs and move closer to the lasting results of bariatric surgery.

The Quest for a Multi-Target Solution

Current weight loss drugs, including Ozempic and Wegovy, primarily focus on one to three hormone receptors. However, researchers led by Krishna Kumar at Tufts University have identified a fourth target – peptide YY (PYY) – that could significantly improve treatment outcomes. According to the CDC, over 40% of U.S. adults have obesity, highlighting the urgent need for more effective therapies. CDC Obesity Statistics

After eating, our bodies release hormones that act as a “fuel gauge,” regulating glucose levels and signaling fullness. The hormone glucagon-like peptide 1 (GLP-1) stimulates insulin production and glucose uptake. Drugs like Ozempic utilize modified GLP-1 to increase its availability, becoming a first-line treatment for diabetes, as recommended by the American Diabetes Association.

Building on Existing Therapies

GLP-1 also acts on the brain to promote feelings of fullness and slows gastric emptying. However, its weekly injection requirement and potential for nausea lead many – up to 40% – to discontinue use, according to Kumar. To address this, researchers created Mounjaro/Zepbound (tirzepatide), a chimera combining GLP-1 and glucose-dependent insulinotropic peptide (GIP), reducing nausea and improving tolerability.

Further advancements led to retatrudide, a chimera incorporating GLP-1, GIP, and glucagon. While glucagon typically raises blood glucose, it also boosts energy expenditure, raises body temperature, and suppresses appetite. Combining it with GLP-1 and GIP neutralizes the glucose-increasing effect, maximizing weight loss potential. Clinical trials suggest retatrudide can achieve up to 24% weight loss, compared to 6-15% with original GLP-1 drugs.

Adding PYY to the Equation

“The goal that people are trying to shoot for is bariatric surgery,” said Kumar. This invasive procedure reduces stomach size, achieving up to 30% weight loss. Current injectable drugs fall short of this standard, prompting the Tufts team to explore the addition of PYY.

PYY, secreted by the gut after meals, reduces appetite and slows stomach emptying through different mechanisms than GLP-1 or GIP. It may also directly promote fat burning. Blending PYY’s structure into a chimera with GLP-1, GIP, and glucagon proved challenging, but the team successfully created a ‘tetra-functional’ clinical candidate by joining two peptide segments.

“One of the limitations of the current drugs is that individual variation, possibly including how people express target receptors or respond to their corresponding hormones, can lead to lesser than desired weight loss outcomes in many patients,”

—Martin Beinborn, Visiting Scholar

Beinborn also noted that weight regain after discontinuing current drugs is a concern, and a multi-chimera approach could potentially offer more lasting results, approaching the effectiveness of bariatric surgery. Lifestyle changes remain crucial for sustained weight management and preserving muscle and bone mass.