GLP-1s don't work for everyone: Why, and what to do?

Combo treatment may work best for those who don’t respond to GLP-1s alone, a recent review suggests. Image credit: Lajst/Getty Images This article originally appeared on Medical News Today Over the past few years, GLP-1 receptor agonists have been growing in popularity for weight loss.

While many people lose between 5-15% of their starting body weight while on a GLP-1, as much as 20% of people may not respond to the drug. Recent research has found that a person’s genetic makeup may explain why some people do not respond to GLP-1 drugs.

A new review suggests that taking both a GLP-1 medication, and a medication that combines both naltrexone and bupropion into one pill, may be helpful for those who are not responding to GLP-1s alone. Over the last few years, glucagon-like peptide-1 (GLP-1) receptor agonists have been growing in popularity for not only treating type 2 diabetes but also for weight loss .

Recent surveys show that about one in every eight adults in the United States — or 12% — are currently taking a GLP-1 medication like Wegovy or Zepbound for weight loss or treatment of a chronic condition. Past research shows that most people taking a GLP-1 drug can expect to lose between 5% to 15% of their starting body weight over 1 year.

However, there is a percentage, as much as 20% of people taking GLP-1s , who may not respond to the drug. According to a study recently published in Nature , a person’s genetic makeup may dictate to what extent they respond to GLP-1 treatment.

Another recent paper, a review published in the journal Obesity Science and Practice , says that taking both a GLP-1 drug, and a medication that combines both naltrexone and bupropion into one pill, may be helpful for those who are not responding to GLP-1s alone. What is Contrave?

In this review, researchers provided an overview of how gut hormone analogs like GLP-1 medications and Contrave — a fixed‐dose, extended‐release combination of naltrexone and bupropion (NB‐ER) — impact eating behavior and the gut-brain axis . “Contrave is a medication that acts to alter [the] brain signal ( dopamine pathway ) in the part of the brain ( hypothalamus ) responsible for controlling how hungry we feel and how much energy we burn, as well as in the part of the brain ( mesolimbic system ) that controls how much pleasure we feel while eating certain foods and how compulsive we feel in repeatedly seeking the same pleasure,” Muzamil Hussain , PhD, a clinical research fellow diabetes and obesity at Ulster University in the United Kingdom, and co-author of this study, told Medical News Today .

“By altering these signals in the brain, cumulatively, Contrave promotes fullness, and reduces food cravings, hence causing weight loss,” Hussain argued. “For example, some patients may crave fatty or sugary foods because their brain associates these with pleasure,” he continued.

“Contrave dampens this brain signal and makes eating fatty food or sugary food less satisfying (less pleasurable) and reduces the urge to ‘comfort eat’ or crave these foods.” A multi-pronged approach to treating obesity Through this study, researchers make the case for a combined approach, using both gut hormone analogs like GLP-1s, and NB-ER at the same time, to treat obesity “Combining NB-ER with GLP-1 makes mechanistic sense because GLP-1 primarily makes a person feel full faster and decreases hunger, while NB-ER reduces food cravings,” Hussain explained. “Hence, this combination can potentially help patients who struggle with binge eating/impulsive ( hedonic ) eating or food cravings.

It can also be useful for those who did not achieve at least 5% weight loss with (a) GLP-1 alone.” “A significant number of patients have suboptimal responses to GLP-1 therapies. This means that these patients did not achieve enough weight loss to provide them benefit in risk reduction for obesity associated conditions like diabetes and heart disease, while using [a] GLP-1 therapy alone.

This is reason enough for the scientific community to keep investigating ways of finding alternative and adjunctive treatments to cater to the medical needs of this patient population.” – Muzamil Hussain, PhD “Obesity treatment is not a one size fits all; we need to come up with a multi-pronged approach targeting multiple pathways to bring meaningful health benefits specially for those patients with sub-optimal response to GLP1s alone,” Hussain added. “NB-ER and GLP-1 combination therapy can be one of the potential options in this approach.” There is no single obesity therapy that works for everyone MNT had the opportunity to speak with Mir Ali , MD, a bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, CA, about the recent review.

Ali, who was not involved in the research, commented that the review’s conclusion reaffirms what he has seen in his own practice: Patients on combination medication therapy tend to see better results. “Obesity is a chronic, pervasive health concern, and there is no single therapy that works for every patient,” he explained.

“Due to the variability in response and other factors, finding new, more effective interventions is always a worthwhile effort.” Jennifer Cheng , DO, chief of endocrinology at Hackensack Meridian Jersey Shore University Medical Center in New Jersey, agreed that obesity and weight loss are multifactorial, and there is still research needed to help determine who will be successful in weight loss and who will not respond. “As someone who treats these people regularly, I have personally seen the struggles that patients have in trying to lose weight,” Cheng, who was likewise not involved in the review, told MNT .

“There is a high degree of frustration when people are taking the time to administer medication and are not able to achieve the results they are expecting. Certain people are poor responders, and it is not always possible to predict who will, and who will not, respond appropriately,” she added.

“It makes sense that adding on secondary therapy or a combination of therapies could assist certain patients with a personalized approach to weight loss,” Cheng continued. “People should work with their doctors to determine the best plan of care.” Cheng said it is also important to determine the reasons why there could be poor response to a medication, so that further weight loss can be achieved for these patients.

“It is also important to identify these factors so that people can use alternatives or combined therapies immediately,” she explained. “Targeted and personalized medical therapy should be initiated sooner to help patients achieve results.”