Weight loss doses It’s the latest craze to shed a few pounds. Its effect has been dramatic with drugs like Ozempic and Wegovy (semaglutide) causing users to lose up to 15% body fat on average.
Semaglutide, a glucagon-like peptide 1 (GLP-1 A receptor agonist drug), which mimics the action of a natural gut hormone released after eating.
This gut hormone triggers multiple physiological responses that play a role in regulating body weight, such as releasing insulin to help control blood sugar levels, slowing stomach emptying (so we feel full longer) and even telling the brain’s hunger centers to suppress appetite.
But although GLP-1 drugs are effective, not everyone who takes them will lose a significant amount of weight. So-called “non-responders” are people who lose less than 5% of their body weight after about six months of treatment at the highest tolerated dose. Research indicates that between 10% and 30% of patients belong to this group.
Many people who are classified as non-responders to GLP-1 receptor agonists such as semaglutide do not take the medication correctly or stop treatment before the appropriate therapeutic effect is achieved. Studies show that up to 20-60% of people stop treatment within the first year, and the use of the drug in doses below the recommended amounts is widespread.
Certain metabolic problems such as insulin resistance, where the body’s cells stop responding properly to insulin, may also prevent semaglutide from working. Sleep disturbance can also inhibit the drug’s action, as lack of sleep has been shown to delay the release of the body’s natural GLP-1 hormone.
People who take other medications, such as corticosteroids and psychotropic medications (such as antidepressants) that can cause weight gain, may also find that GLP-1 medications do not work as well for them.
But these are not the only reasons why a person may be classified as a non-responder.
Interestingly, gender may play a role in how a person responds to these medications, as research has shown that women who take semaglutide consistently lose more weight than men.
A review of 47 randomized controlled trials including more than 23,000 patients found that the greatest weight-loss effect of GLP-1 drugs occurred in participants who were younger, female, and had not been diagnosed with diabetes (and therefore had better insulin sensitivity).
One of the reasons women react better is because their estrogen levels are higher. This hormone improves insulin sensitivity and stimulates the secretion of GLP-1.
Another reason why some people respond poorly to GLP-1 drugs is their genetic makeup.
Scientists have identified variants in the gene coding for the enzyme PAM (peptidylglycine alpha monooxygenase) that appear to cause GLP-1 resistance. This genetic change occurs in approximately 10% of the population.
People with this genetic change have higher circulating levels of GLP-1 but without the expected biological effect. This means that more GLP-1 hormone is needed to achieve the same response in people who do not have the mutation. This indicates clear resistance to the hormone.
Research that looked at the genetics of nearly 28,000 people taking GLP-1 also identified genetic problems in another set of receptor genes called GLP-1R and GIPR.
This genetic problem caused differences in weight loss and side effects. Those with these genetic problems had a higher body mass index (BMI) and body mass on average, and were more likely to develop type 1 diabetes and other metabolic problems. Such genetic differences may explain why some people fail to lose any weight when taking GLP-1 medication.
Another factor that may contribute to non-responders relates to the causes of obesity itself. Our body operates based on four different types of hunger. If the drug targets something that is not the primary cause of a person’s obesity, the response will be small.
The first type is our basic slow hunger, which is the minimum number of calories our body must consume in order to function (also known as our metabolic rate). Another type of hunger is the hungry gut, which is associated with the real physiological need to eat. The way we eat can also be driven by our mind (known as the hungry brain, where we eat out of habit or stress) or our emotions (known as emotional hunger, where we eat to cope with what we’re feeling).
For patients suffering from emotional hunger, GLP-1 medications do not address the root cause of the anxiety and depression that drives that person to overeat. According to one observational study conducted in Japan, emotional eaters were less likely to see significant weight changes when using GLP-1 drug therapy.
About the author
Nadine Waheeda is a Senior Lecturer in Genetics and Molecular Biology, Kingston University. Ahmed Al-BadawiHe is Senior Lecturer in Cancer Biology and Clinical Biochemistry, Kingston University. This article was first published by Conversation It is republished under a Creative Commons license. Read Original article.
So incorporating cognitive behavioral therapy may be important for people who struggle with emotional hunger and use GLP-1 medication. For hungry bowel patients, a diet high in protein and fiber can enhance the effectiveness of the medication.
For patients with a hungry brain, switching to dual agonists such as terzipatide (commercially known as Mongaro), which targets two digestive hormones, GLP-1 and glucose-dependent insulinotropic peptide (GIP), may be beneficial. For slow starvation, resistance training can increase your resting metabolic rate.
While weight loss medications have proven effective for many, the fact that they do not work for everyone highlights how important it is to move toward developing precision obesity medicine. This may include analyzing a patient’s unique genes and lifestyle patterns to match them to the correct medication. While genetic testing for variants associated with non-response is not common, it represents the next step in helping to ensure patients get treatments that work best for them.
