Why GLP-1s don’t work for everyone

While glucagon-like peptide-1s have been widely celebrated for transforming weight loss, some who attempt to use the medications find themselves in a less-studied patient category called nonresponders. This minority of people haven’t experienced any significant change in weight even after adjusting their dose or switching brands.

What are the influencing factors?

Between “9% and a third of participants” in clinical trials for GLP-1 weight-loss drugs lose less than 5% of their body weight after months of use, which is the threshold associated with health improvements, said The Guardian. Now, researchers are “trying to work out why” the drugs are ineffective for nonresponders — a discovery that could help doctors “tailor the use of the drugs, maximize cost-effectiveness and reduce side effects.”

The drug’s lack of efficacy cannot be blamed on patients, said Alexander Miras, an obesity expert at Ulster University, to The Guardian. If the drug does not “reduce hunger and food intake for someone,” it is “just not going to work.”

For now, the “short answer” to why some people don’t respond is that “we don’t really know,” said Miras. Research suggests that factors such as “motivation, intelligence, education and socioeconomics” are not predictors of how patients would “respond to GLP-1 medications.”

Other characteristics such as age, sex and whether or not someone has Type 2 diabetes do appear to have an effect. Studies have also suggested “ancestry might have an impact,” with the medications “most effective in people of European ancestry and least effective in people of African American ancestry,” said The Guardian.

Some may be jumping the gun, however. Many people labeled as nonresponders simply “do not take the medication correctly” or “discontinue treatment before adequate therapeutic effect can be achieved,” said Kingston University biologists Nadine Wehida and Ahmed Elbediwy at The Conversation. Studies show up to 20% to 60% of people “stop treatment within the first year” amid “widespread use of the drug in doses below the recommended amounts.”

Is there hope for nonresponders?

There is “no reliable way” to predict what group one will fall into when trying GLP-1s, said Stanford Medicine News Center. The good news is “you don’t have to wait long to find out.” In general, higher doses produce better results, so doctors “typically start patients low and increase gradually, watching for side effects.”

If the dose is not associated with any weight loss, “waiting three months on the same dose is not going to give you more answers,” said Stanford Medicine endocrinologist Sun Kim to the department’s News Center. You should “increase the dose and reassess.” Whether or not it’s working tends to become clear within the first few weeks.

Certain medical factors such as “thyroid disorders” can “disrupt metabolism,” said Yale Medicine. People with “impaired glucose regulation,” including those with diabetes, therefore tend to “lose less weight on these medications.” A less common underlying condition could also be playing a role.

Sometimes, “despite doing everything right,” a patient “just doesn’t respond the way we would hope,” said Avlin Imaeda, a Yale Medicine gastroenterologist. And this phenomenon isn’t “unique to weight-loss medications,” said Yale Medicine. Some patients may not react to “certain blood-pressure drugs, antidepressants or cancer therapies.” Biology is complex, and treatment responses can vary widely.

For those hoping for something to look forward to, a “series of promising new drugs are in development,” said The Guardian. In the meantime, for nonresponders still struggling to lose weight, “weight-loss surgery may be the only option left.”

GLP-1-based drugs not working does not “predict a lack of response to [bariatric] surgery,” said Miras. In the end, it’s “not your fault,” and it’s not the drug’s fault either. “This is purely luck.”