Your Genes May Affect How Well Ozempic and Wegovy Work for You

New research suggests that about 10% of people carry certain genetic variations that could make popular weight loss drugs like Ozempic and Wegovy less effective.

GLP-1 medications have become very popular for managing type 2 diabetes and treating obesity. Drugs in this class, including Ozempic and Wegovy, are widely known for helping people lose weight.

However, a study published in Genome Medicine indicates that these medications may not work for everyone. The findings point to genetics as a possible reason why.

About 1 in 10 people have genetic variations linked to something called “GLP-1 resistance.” These individuals naturally have higher-than-normal levels of the hormone GLP-1, which helps control blood sugar. But despite having more of this hormone, it seems to be less effective at doing its job.

“This matches what I see in my practice, where patients respond very differently to GLP-1 drugs,” said Dr. Mir Ali, a bariatric surgeon and medical director of the MemorialCare Surgical Weight Loss Center in California. He was not involved in the study.

It is not yet clear whether these genetic variations affect weight loss specifically. Doctors usually prescribe higher doses of GLP-1 drugs for weight loss than for diabetes. This study focused mainly on how these drugs and genetic variants affect blood sugar levels.

Genetic Variants and GLP-1 Resistance

The research focused on two genetic variants that affect an enzyme called PAM. This enzyme helps activate several hormones, including GLP-1.

Certain variants of PAM are more common in people with diabetes and may keep the pancreas from releasing insulin properly. The researchers wanted to find out if these same variants also interfere with GLP-1.

Normally, GLP-1 helps control blood sugar, triggers insulin release after meals, slows down stomach emptying, and reduces appetite. GLP-1 drugs are designed to copy these effects.

When researchers looked at people with a specific PAM variant called p.S539W, they expected to find lower GLP-1 levels. Instead, they found higher levels. Even with more GLP-1 in their bodies, these individuals did not lower their blood sugar any faster. They needed more GLP-1 to get the same effect, which suggests they were resistant to it.

“These findings support the idea that some patients may have a natural resistance to these therapies,” said Dr. Robert Glatter, an emergency medicine physician at Lenox Hill Hospital in New York. He was not involved in the study. He added that genetics only explains part of why people respond differently, and genetic testing is not yet ready for everyday use.

More research is needed to confirm how genetic variations affect weight loss with GLP-1s. Still, the findings are promising for the future of obesity treatment.

“The bigger lesson is that obesity treatment is entering an era of precision medicine,” Glatter said. “Instead of asking whether GLP-1 drugs work, doctors are starting to ask who they work best for — and what other options to consider when they don’t.”

Why GLP-1s Don’t Always Work and What Else to Try

Experts shared why some people don’t respond to GLP-1 drugs and what alternatives are available.

What else affects how well GLP-1s work?

Dr. Ali says other factors can include underlying health conditions or patients not taking the medication exactly as prescribed.

Dr. Glatter notes that many people labeled “non-responders” may actually be dealing with issues like not taking a high enough dose, stopping early due to stomach side effects, not taking the drug long enough, or having other metabolic problems such as severe insulin resistance, poor sleep, muscle loss, or weight gain from other medications. Fixing these issues can often restore how well the drug works.

What other options exist if GLP-1s don’t work?

Dr. Ali says weight loss surgery remains the most effective long-term solution for those who qualify.

Dr. Glatter agrees that bariatric surgery, such as sleeve gastrectomy or gastric bypass, should be considered earlier. These procedures lead to average weight loss of 25 to 35% and are the most durable treatments for severe obesity. Surgery also changes how the body handles incretin hormones, increasing GLP-1 activity and improving insulin sensitivity.

Can combining medications help?

Dr. Glatter says that when a single drug isn’t enough, doctors should consider combination therapy. Obesity involves many systems in the body, including appetite, reward signals, gut-brain hormones, and energy use. Combining GLP-1 drugs with other medications like phentermine, topiramate, or bupropion-naltrexone targets different pathways and is backed by growing evidence.

Dr. Ali adds that if surgery is not an option, doctors can try drugs that target more than one receptor, such as Zepbound, or a combination of different medications.

What are other proven weight loss strategies?

Dr. Ali says most weight loss comes from diet changes — mainly cutting back on carbs and sugar while eating more protein and vegetables. Adding both aerobic and strength training exercise helps burn calories and prevent muscle loss.

Dr. Glatter recommends following the Mediterranean, DASH, or MIND diet, along with regular strength training, staying hydrated, and watching calorie intake to preserve muscle. Even without GLP-1 drugs, these lifestyle habits are effective for weight loss and maintaining muscle mass.