Ozempic, Wegovy: Why GLP-1 drugs don’t work for everyone

• GLP-1 therapeutics do not necessarily work for everyone.
• A new study suggests that about 10% of people carry a genetic variation and explains why.
• A new review suggests that certain combination approaches to obesity pharmacotherapy may be effective even when GLP-1 drugs are not.
• Experts share recommendations on alternative weight loss strategies.

GLP-1 drugs have exploded in popularity for the management of type 2 diabetes and the treatment of obesity.

One reason for the popularity of this class of drugs, which includes Ozempic and Wegovy, is their widespread success in weight loss.

However, a new study published in the journal Genome Medicine shows that GLP-1 drugs may not work for everyone. This finding suggests that certain genetic factors may provide an explanation.

Approximately 10% of people have genetic mutations associated with “GLP-1 resistance.” These people appear to have higher than normal levels of the glucagon-like peptide-1 (GLP-1) hormone. GLP-1 helps regulate blood sugar levels. In contrast, despite high GLP-1 levels, this hormone appears to be less effective.

“This is consistent with my clinical experience where we frequently see mixed reactions to GLP-1 drugs,” said Mir Ali, MD, bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, California. Ali was not involved in this study.

It is unknown whether these genetic variations affect weight loss. GLP-1 drugs are generally prescribed in higher doses for weight loss rather than diabetes management. The current study focused on GLP-1 and how these genetic mutations affect blood sugar levels.

This study focused on two genetic mutations that affect the enzyme peptidylglycine alpha amidation monooxygenase (PAM).

PAM is responsible for activating various hormones, including GLP-1.

Certain variants of PAM are more common in diabetics and can impair the release of insulin from the pancreas. The research team sought to find out whether these mutants also disrupt GLP-1.

In addition to helping regulate blood sugar, GLP-1 stimulates insulin release after meals, slows stomach emptying, and reduces appetite. GLP-1 drugs are made to mimic the effects of this hormone.

When the research team analyzed individuals with a PAM mutation called p.S539W, they expected to find that they had low GLP-1 levels. However, GLP-1 levels were found to be elevated in these people.

They also found that even with high GLP-1 levels, participants did not experience a faster decline in blood sugar levels. More GLP-1 was required to achieve the same biological effect, indicating that the participants were GLP-1 resistant.

“These findings support the idea that some patients may have a partial biological resistance to incretin-based treatments,” said Robert Glatter, MD, an attending physician in the Department of Emergency Medicine at Lenox Hill Hospital in New York City and assistant professor of emergency medicine at the Zucker School of Medicine at Hofstra/Northwell. Glatter was not involved in the study.

“Yet, genetics can only partially explain treatment heterogeneity, and routine pharmacogenomic screening is not yet ready for widespread clinical use,” he added.

Further studies are needed to verify the impact of genetic variation on GLP-1-induced weight loss. Still, the results of this study show promise for the future of obesity treatment.

“The broad lesson from recent research is that obesity treatment is entering the era of precision medicine,” Glatter said. “Instead of asking whether GLP-1 drugs work, clinicians are starting to ask who they work best for, and what alternative routes should they consider if the response is incomplete.”

We asked experts to explain why GLP-1 isn’t always effective for weight loss and what alternatives are available. These interviews have been lightly edited for clarity.

Ali: Other factors may include underlying medical conditions or the patient not using the medication as prescribed.

Smoother: In practice, many patients classified as “non-responders” to GLP-1 therapy experience premature discontinuation due to incomplete dosing, gastrointestinal side effects, insufficient treatment duration, or competing metabolic factors such as severe insulin resistance, sleep disturbances, sarcopenia, and drug-related weight gain.

Addressing these causes often reverses the effects of treatment.

Ali: If the patient meets the criteria, surgical debulking remains the most effective solution in the long term.

Smoother: Another important option worth considering sooner rather than later is metabolic and bariatric surgery. Too often surgery is positioned as a last resort after medication failure, but it is better understood as a parallel treatment strategy within the same continuum of treatment.

Surgery such as sleeve gastrectomy and Roux-en-Y gastric bypass yield an average weight loss of 25-35% and remain the most durable interventions available for severe obesity and obesity-related metabolic diseases.

Importantly, surgery also alters incretin signaling itself, increasing GLP-1 activity and improving insulin sensitivity in a manner that is complementary to drug therapy.

Smoother: If response is limited despite optimization, clinicians should consider transitioning from monotherapy.

Obesity is a network disease involving appetite regulation, reward signaling, gut-brain hormones, and energy expenditure pathways.

Concomitant drug therapy — such as combinations of incretin agents with phentermine, topiramate, or bupropion-naltrexone — target complementary mechanisms and are increasingly supported by mechanistic and clinical evidence. Combination therapy does not represent a treatment escalation alone, but reflects a broader shift toward multidisciplinary metabolic care.

Ali: If surgery is not an option, you can try drugs that stimulate multiple receptors (such as Zepbound) or combinations of different drugs.

Ali: Most of the weight loss is facilitated by dietary modification, which focuses primarily on protein and vegetables while reducing carbohydrate and sugar intake. Adding both aerobic and resistance exercise will burn more calories and reduce muscle loss.

Smoother: Additional approaches to reduce weight and manage the cardiometabolic aspects of obesity include adhering to a Mediterranean, DASH, or MIND diet, as well as adequate strength training, close monitoring of hydration status, and caloric intake to maintain and prevent muscle loss, especially while taking GLP-1.

Even if you choose not to take GLP-1 to manage weight loss, adherence to a Mediterranean-style diet, adequate hydration, and strength training combined with aerobic exercise are recommended for weight loss and muscle mass maintenance.