How Weight Loss Drugs Differ

A new generation of weight loss drugs has revolutionized obesity treatment and expanded therapeutic options for weight management. In her recent article for Nature.com, reporter Mariana Lenharo lays out how emerging research now highlights that these medications, despite their similar mechanisms, can vary in effectiveness.

Drugs like semaglutide and tirzepatide, designed to treat obesity and metabolic disorders, work by mimicking a natural hormone called glucagon-like peptide-1 (GLP-1). Yet, studies have revealed notable differences in their impact. Some are better at preventing type 2 diabetes, and certain drugs promote greater weight loss than others. Research also indicates that older GLP-1 drugs may be more effective in treating neurodegenerative conditions such as Parkinson’s disease than newer alternatives.

Understanding these differences can help physicians better tailor treatments, says Dr. Beverly Tchang, an endocrinologist at Weill Cornell Medicine:

If a patient with obesity has cardiovascular disease, I tend to prescribe semaglutide over tirzepatide, because we have data.

Dr. Tchang cited a study that shows semaglutide reduces the risk of severe cardiovascular events in patients with cardiovascular conditions. For a patient with sleep apnea, the choice might be different, Dr. Tchang notes, referring to research indicating that tirzepatide helps reduce sleep apnea symptoms in obese individuals.

Comparing effectiveness

Among the most popular weight loss drugs are semaglutide, marketed as Ozempic and Wegovy; and tirzepatide, sold as Mounjaro and Zepbound. A recent study found that tirzepatide is more effective than semaglutide in preventing type 2 diabetes in obese patients. Another analysis showed that tirzepatide leads to greater weight loss than semaglutide in people with overweight and obesity. Researchers are now anticipating results from a randomized controlled trial comparing the two drugs for weight loss, which could provide a more definitive answer than earlier retrospective studies.

Both semaglutide and tirzepatide mimic GLP-1, which regulates blood sugar and suppresses appetite. This allows these drugs to activate receptors that GLP-1 normally targets. However, tirzepatide also mimics another hormone called gastric inhibitory polypeptide (GIP), involved in fat metabolism. As a result, tirzepatide activates both GLP-1 and GIP receptors.

But attributing tirzepatide’s greater potency solely to its dual hormone targeting oversimplifies its function, says Dr. Tchang. Tirzepatide does not equally activate GLP-1 and GIP receptors; it binds more effectively with GIP receptors. One theory suggests that its GIP activity enhances GLP-1-driven weight loss, despite weaker activation of the GLP-1 receptor.

Amgen, a biotechnology company, is developing an experimental drug that also targets GLP-1 and GIP receptors. Unlike tirzepatide, this drug blocks GIP receptors while activating GLP-1 receptors, and it has shown promising weight loss results in early clinical trials.

Researchers are now grappling with why significant weight loss can occur both by activating GIP and GLP-1 receptors and by activating GLP-1 while blocking GIP receptors. “There are theories, but we still have much to learn,” says Daniel Drucker, an endocrinologist at the University of Toronto.

Protecting the brain

GLP-1 drugs not only promote weight loss but also reduce inflammation, which may explain their potential to slow neurodegenerative diseases like Parkinson’s and Alzheimer’s, both of which involve brain inflammation.

In one small trial, the GLP-1 drug exenatide improved symptoms in people with moderate Parkinson’s disease. Exenatide, which was approved by the U.S. Food and Drug Administration in 2005, was the first GLP-1 drug on the market. A small trial of another GLP-1 drug, liraglutide, slowed cognitive decline in people with mild Alzheimer’s disease by up to 18% over one year.

Some researchers believe that the better a GLP-1 drug can penetrate the brain, the more effective it might be in treating neurodegenerative diseases. While it remains unclear how far these drugs can reach into the brain, animal studies suggest differences between GLP-1 medications in this regard.

Exenatide, for instance, appears to cross the blood-brain barrier, a protective shield that regulates which substances can enter the brain from the bloodstream. Christian Hölscher, a neuroscientist at the Henan Academy of Innovations in Medical Science in China, credits exenatide’s initial success in treating Parkinson’s to this ability.

Hölscher points out that a longer-lasting version of exenatide was less effective in treating Parkinson’s because it is a larger molecule that cannot penetrate the brain. He says:

This shows how crucial it is for the drug to reach the damaged areas of the brain to improve and protect neurons.

He also notes that semaglutide may not cross the blood-brain barrier, making it unlikely to be as effective against Alzheimer’s or Parkinson’s. However, not all researchers agree. “We don’t have solid data linking brain penetration with effectiveness in neurodegenerative diseases,” says Drucker.

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Source: “How rival weight-loss drugs fare at treating obesity, diabetes and more,” Nature.com, 09/03/24
Source: “The Weight Loss Drug That Can Prevent Diabetes,” TIME, 09/04/24
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