4 Reasons Weight Loss Drugs Aren't Working for You

Many people who take GLP-1 receptor agonist drugs such as Wegovy (semaglutide) and Zepbound (tirzepatide) will lose significant weight and see multiple health improvements. However, some may not see much change in their body weight or overall health, even after months on the medication.

In clinical trials, more than 13% of participants using Wegovy and 9% on Zepbound and Mounjaro were considered “non-responders” to the medications. This means they didn’t lose 5% or more of their body weight within the first three months of treatment.

No medication works perfectly for everyone, and the new class of weight management and diabetes drugs is no different, said David Lau, MD, PhD, professor emeritus and director of the Julia McFarlane Diabetes Research Centre at the University of Calgary.

Scientists are still trying to understand why some people can tolerate and respond to GLP-1s more than others. In the meantime, there are some lifestyle factors that are within your control. Here are some questions to ask yourself if you’re not seeing the weight loss you want on a GLP-1 drug.

Are You Eating, Exercising, and Sleeping Well?

GLP-1 drugs can help to control appetite and hunger, but they aren’t a cure-all. Tending to your health in other ways may determine how beneficial the drugs are for you.

When comparing your GLP-1 responsiveness to clinical study results, it’s important to know that participants in those trials also received diet and exercise counseling.

“Lifestyle intervention and lifestyle modification remain the foundation of therapy for people living with overweight and obesity,” Lau said.

Many people who take GLP-1 drugs experience a reduction in their “food noise" or cravings for fatty and sugary foods, Lau said. But if someone continues to eat calorie-dense foods over nutrition-rich options, they may struggle to lose weight.

Prioritizing protein intake is also important for managing weight in a sustainable and healthy way, said Jorge Moreno, MD, an obesity medicine specialist and assistant professor at the Yale School of Medicine. Getting adequate protein can help stave off hunger after meals, reducing the tendency to snack. It’s also important for avoiding muscle loss.

Moreno said exercise is the “number one” most important factor for maintaining weight loss. Strength training can build muscle and improve metabolism, bone strength, blood sugar control, and more. Aerobic exercise carries benefits, including improved heart and mental health.

Studies show that people who exercise regularly not only lose more weight when taking a GLP-1 drug, but they also tend to keep the weight off more effectively.

Sleeping poorly and being stressed out can also limit the body’s ability to lose weight. A lack of rest often leads to an imbalance in hunger hormones, which stimulates appetite and encourages fat storage. If you’re stressed, your body may release hormones that cause you to feel hungrier or conserve energy by storing calories.

“When you don’t sleep well, you may be hungrier the next day. You may be tired, so you don’t have the energy to exercise as much as you want to. You’re not able to focus on all the things that you want to do, like eat better. Some people who are super swamped may not be consistent with taking the medication,” Moreno said. “All of these things matter, and every little bit adds up.”

If you’re exercising, eating well, and sleeping well, and yet you’re not responding to GLP-1s, this is a sign that your body is not going to respond, Moreno explained.

Are You Taking the Right Dose?

If you just started taking a GLP-1 drug and aren’t seeing results yet, you may just need to be patient. Most people start losing weight after taking the drug for about three weeks.  

“It's only after a trial of taking the medication that we can identify who responds and who doesn’t respond,” Lau said.

Sometimes, the key is to adjust your dose. In clinical trials, 85% of people taking 5 milligrams of tirzepatide (sold as Zepbound and Mounjaro) saw meaningful weight loss, compared to 91% of those at a 15-milligram dose.

Lau said some people may just need a higher dose of GLP-1 medication for their body to start responding to it. Researchers are now studying whether a 7.2-milligram dose of semaglutide—a dose three times greater than Wegovy—will cause even more responsiveness.

“If you overload the system with more GLP-1, you’re more likely to have the receptors open and bind to the GLP-1. Therefore, you would elicit a response that you otherwise might not have at a lower dose of the drug,” Lau said. “This is still a subject of tremendous research.”

If you once lost weight while taking a GLP-1 drug and now no longer do, you may have hit a weight loss plateau. That doesn’t mean the medication isn’t working for you. At some point, weight loss will always peter out.

If that happens before you reach your health goals, you can work with your doctor to find solutions. They may suggest switching you to a different medication, adding another non-GLP-1 medication, undergoing bariatric surgery, or making lifestyle changes to keep managing your weight.

Is Your GLP-1 Use Consistent?

GLP-1 drugs are effective only as long as they’re taken consistently. Pausing the medication or inconsistent use can lead to weight regain or poorer glycemic control. In one study, people who paused tirzepatide regained about 15% of their body weight in the following four months.

“This treatment is meant for lifetime unless you are willing to return to your original weight,” Steven Heymsfield, MD, a professor of metabolism and body composition at Louisiana State University, told Verywell in an email. “Compliance is the number one issue, and lack of compliance has many causes.”

Many people experience gastrointestinal and other side effects when taking a GLP-1 medication. For some people, those side effects are uncomfortable enough that they choose to stop the medication.

Sometimes, the price tag keeps people from consistently accessing their medication. Most health insurers don’t cover weight management drugs, and routinely paying upwards of $1,000 per month out of pocket is untenable for many people.

It’s also worth checking that the medication you’re taking is the pure version of the drug you were prescribed, Heymsfield said. Prescriptions filled by compounding pharmacies may use ingredients like semaglutide sodium, which are not proven to work and may be unsafe.

Do You Have Other Health Conditions That Affect Weight Loss?

Sometimes, other health conditions can affect how easy it is for someone to lose weight.

People who have type 2 diabetes before starting a GLP-1 medication tend to lose less weight than those with obesity and no diabetes. Taking insulin can also make it harder for someone to lose weight.

“Hundreds” of psychiatric medications are also weight promoting, Moreno said.

If someone needs to take a weight-promoting medication for a different condition, Moreno said he may prescribe an older GLP-1 drug that is better suited for their needs. For instance, people with depression and anxiety could see mental health benefits as well as weight loss when taking Contrave (bupropion/naltrexone). Stacking several medications can sometimes help people manage both their weight and other conditions simultaneously.

Understand What’s Realistic

The average weight loss reported in the studies is just that—an average. Not everyone will lose 15% or 20% of their body weight.

Individuals who cannot tolerate the highest doses of semaglutide or tirzepatide may find it hard to achieve the substantial weight loss reported in the clinical trials by using those drugs alone.

On the other hand, there are “super responders” who lose far more body weight than the average. Much of the difference in response may have to do with genetic factors and other biological mechanisms scientists don’t yet understand. For example, some people metabolize or process drugs faster than others. And people may have different levels of sensitivity to hormones.

Scientists are working to untangle all the factors that contribute to weight management success. Those findings could help clinicians to personalize their patient’s health care.

“I don’t want patients to focus so much on the exact number and meeting an exact weight loss goal,” Moreno said. “They should look for other improvement variables like: Are they able to go up the stairs easier? Are they able to play with their grandkids? Are they able to treat their diabetes, cholesterol, and blood pressure better?”