The '3rd generation' of weight loss drugs

Anita Courcoulas, MD, defines GLP-1s as "generation one;" dual GLP-1 and GIPs as the second; and a triple threat of GLP-1, GIP and GCGRs as the third generation of weight loss drugs. 

Dr. Courcoulas is chief of Pittsburgh-based UPMC's minimally invasive bariatric and general surgery program. She told Becker's the next class of anti-obesity medications are finally reaching weight loss outcomes seen from gastric sleeve and bypass procedures, the two most common surgeries for trimming pounds. 

Glucagon-like peptide-1 receptor agonists are medications currently approved for Type 2 diabetes, chronic weight management and, in Wegovy's case, cardiovascular disease. The first GLP-1 to snag FDA approval was Byetta (exenatide) in 2005, but in recent years, the medications surged in popularity. 

Most GLP-1s are only approved for Type 2 diabetes, such as Ozempic and Trulicity, but demand is high for off-label weight loss uses. They average 15% weight loss among patients, Dr. Courcoulas said. 

Newer therapies are glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonists. These include Mounjaro and Zepbound — an Eli Lilly diabetes and weight loss drug, respectively — and help patients lose 20% to 22% of their body weight. That's what Dr. Courcoulas calls the "second generation." 

The next generation is in phase 3 trials, she said. Experimental therapies are combining GLP-1 and GIPs with glucagon and glucagon receptors, or GCGRs. One example is Eli Lilly's drug candidate retatrutide, which reduced study participants' weight by 24.2% after 48 weeks — the most significant weight loss results compared to other drugs on the market. 

Gastric sleeve operations help patients lose 30% of their weight before leveling off at 20% to 25% after five to 10 years, Dr. Courcoulas said, and gastric bypass surgeries result in up to 38% initial weight loss and 30% leveled weight loss. 

Pharmacological weight loss tools in late-stage trials, such as retatrutide, are also showing higher efficacy in people with higher weights. 

"It's exciting because the people who need to lose the most weight appear to be losing more weight with these drugs," she said. "I think what we will see in the next number of years is that some of these drugs will have even bigger, more weight loss."

Dr. Courcoulas said the biggest unknown is long-term durability of these medications, a concern other bariatric experts have raised. 

She expects GLP-GIP-GCGR medications to gain approval and enter the U.S. market next year. 

"I think it's very exciting to realize there are medications that are under investigation now that could come to market that could have even better weight loss results than the two drug [classes] we're seeing now," Dr. Courcoulas said.

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