Although most patients in your practice will find success with GLP-1 medications, some may not respond well to them. When defining nonresponsiveness, a study said that for weight loss, nonresponse is characterized as failing to lose at least 5% of body weight after 3 months of GLP-1 therapy.

“With any treatment or medication, there will always be individuals that don’t respond to treatment, though complete nonresponders to GLP-1 medications are rare,” said Samantha P. Flanagan, DO, assistant professor of clinical family & community medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia.

Flanagan said they define a nonresponder as someone who doesn’t achieve a 5% or greater total body weight loss. By this definition, about 9%-17% of patients treated with Zepbound (tirzepatide) are nonresponders, and about 13%-17% of patients treated with Wegovy (semaglutide) are nonresponders, she said.

Should the Primary Care Physician (PCP) Order Tests to Find the Cause?

To find the cause of a patient’s nonresponsiveness, begin with a thorough history and exploration of potential phenotypes driving obesity, said Ryan M. Kane, MD, MPH, MHSc, assistant professor at the Food is Medicine Institute at the Friedman School of Nutrition Science and Policy at Tufts University in Boston. Additionally, providers should consider genetic testing based on family history and additional laboratory testing to assess additional metabolic diseases, including thyroid, Cushing disease, steatotic liver disease, and diabetes, he said.

Also, when examining major GLP-1 clinical trials, patients with diabetes tend to lose less weight than patients without diabetes, cited Kane. He added that there are also “late responders” to GLP-1 therapy for weight loss, where it takes more than 12 weeks to reach at least 5% weight reduction. Studies have revealed that the average time to reach 5% weight reduction for late responders was 24.8 ± 12.7 weeks.

Clinical Reasons for Lack of Patient Response

There could be biological, genetic, and other factors that could be affecting the efficacy of these medications. Here are some factors you may want to consider when treating your patients.

• Biological variation in GLP-1 receptors: Some people naturally have fewer or less sensitive GLP-1 receptors, meaning the medication’s appetite-lowering and gastric-slowing effects may not work as strongly, said Kane. “You can think of this as being similar to how some people respond differently to blood pressure or cholesterol medications,” he said.
• Genetic differences affecting appetite hormones: Variants in genes linked to appetite regulation can blunt how strongly GLP-1s reduce hunger, he said.
• Coexisting medical mechanisms: Medical conditions such as hypothyroidism, Cushing syndrome, or polycystic ovary syndrome, along with certain medicines, such as steroids, antipsychotics, and some diabetes drugs, can biologically interfere with the weight loss achieved through GLP-1 medications. “Even well-controlled depression or chronic stress can raise cortisol and blunt weight-loss effects,” Kane continued.
• Insufficient dose or inadequate titration: Some patients need the full therapeutic dose before the appetite-reducing effect fully appears. Stopping early because of side effects or staying too long at a lower dose can make the medication appear ineffective, Kane said.
• Lifestyle actions or barriers: GLP-1s work in many ways to reduce appetite, but they don’t address the challenges of our food environment, such as access to highly processed foods and limited access to healthy, minimally processed foods like vegetables, fruits, nuts, seeds, beans/legumes, and seafood, said Kane. It may be helpful to also speak with patients about specific lifestyle factors that may be affecting weight, such as physical activity, stress, and sleep quality.

How Does Age Play a Factor?

Patients over the age of 75 achieve less weight loss compared to individuals younger than 55 years, said Flanagan. “While a clear reason has not emerged and the lessened response is likely multifactorial, several reasons may exist, including slower metabolic rates seen in older individuals as a result of aging, and lower baseline muscle mass can result in less significant weight loss,” Flanagan said. 

Assessing a Patient Plateau or Nonresponse

A careful assessment is suggested.

“I would titrate meds to max dose,” said Susan Spratt, MD, professor of medicine, Division of Endocrinology, Metabolism, and Nutrition at Duke School of Medicine in Durham, North Carolina. “That could take 3-5 months, depending on medication and side effects. Patients who don’t respond to a lower dose may respond to higher doses.”

What Are Possible Suggestions to Kick-Start the Medication?

Spratt said there are ways to improve the medication’s effectiveness. They include:

• Exercising
• Planning on eating half of the plate
• Prioritizing protein
• Avoiding fatty foods
• Reviewing medications: If a patient is taking medicines that could cause weight gain, consider stopping them. This can include glucocorticoids and some depression meds, Spratt said.

When Do You Accept the Patient Isn’t Responding?

If your patient is not responding even after switching to another brand of GLP-1 medication, then consider that they aren’t fit for this class of meds. “If A1c has not changed, weight has not changed, and no effects are seen, I would consider stopping,” said Spratt.

What Additional Information Can a PCP Provide?

Reassure your patient that it’s not their fault and share that other options are available.

“Everyone’s physiology, environment, and circumstances are different,” said Kane. “Fortunately, we have several treatments to try at this time and have more new medications in development. It’s important to give these therapies the best chance of success with supportive, intensive lifestyle therapy, as well as management of potential social drivers of health like food and nutrition insecurity.”

Kane reported receiving research grant funding from the Ardmore Institute of Health. Flanagan reported no disclosures. Spratt serves on the MEDPACE Data Monitoring Board and owns stock in Pfizer, Merck, Johnson & Johnson, and Procter & Gamble.