Glucagon-like peptide-1 (GLP-1) receptor agonist drugs are revolutionizing care for people with obesity, which affects more than 40% of U.S. adults, offering levels of weight loss that were previously difficult to achieve with medication alone. With the advent of oral GLP-1 medications, these drugs are becoming more affordable and accessible than ever. But while GLP-1s are often presented as a universal treatment for obesity, only about one third of patients do well on these drugs. Many people never experience the dramatic weight loss touted for GLP-1s, and 60% experience significant side effects like nausea and vomiting.
New research from the direct-to-consumer DNA testing industry has linked both GLP-1 response and side effect risk to two gene variants, bringing awareness to the greater need for precision medicine in obesity treatment. But while the conversation generated by the recent study is valuable, focusing on two gene variants obscures the more complex gene relationships that drive obesity.
Here’s what we miss if we only focus on one gene variant at a time:
1. At least 10 genes and 1,500 variants impact GLP-1 response. One of the genes currently in the spotlight is the GLP-1 receptor, which helps to regulate the human body’s response to GLP-1 drugs. While new research on one variant of the gene is helping us understand weight loss differences among GLP-1 users, there are multiple variants of that gene and nine other genes connected to GLP-1 response.
The current hype is correct that the GLP-1 receptor gene plays a pivotal role in GLP-1 drug response. But when we look at all 1,500 variants instead of just one, the difference is stark. People who possess one gene variant were recently linked to a weight loss increase of 0.5 kg (about one pound) on GLP-1s, but prior studies of all 1,500 variants have revealed genetic combinations capable of driving 9 kg (about 20 pounds) of weight loss. That’s the difference between being able to explain 5% of why GLP-1 response differs versus having 90% of the answer.
2. Side effects from GLP-1s often signal a bigger mismatch in biology. More than 60% of GLP-1 users experience nausea and vomiting, side effects that play a significant role in whether patients can tolerate long-term GLP-1 use. New research points to a receptor on a second gene, GIP, that predicts nausea for patients taking tirzepatide (Zepbound, Mounjaro). However, only some GLP-1s target both the GLP-1 and GIP receptors. Other popular drugs like semaglutide (Wegovy, Ozempic) only target the GLP-1 receptor. What this means is that a single gene variant can’t explain why so many GLP-1 users experience gastrointestinal side effects.
Instead, it seems that side effects are connected to the bigger picture of a person’s underlying biology. People who need more calories to feel satiated have been observed to experience a higher risk of nausea and headaches. They may also not lose as much weight on certain GLP-1s as people with lower calories-to-satiation scores. What we can learn from this is that drug-induced weight loss often fits certain profiles that go beyond the presence of a single genetic factor.
3. GLP-1 response isn’t a yes-or-no issue. One of the most dangerous possible outcomes of focusing on one gene variant at a time is that some people may think that GLP-1 response either works for them, or doesn’t. Given the serious health problems associated with obesity and the potential benefits of drug-induced weight loss, it’s vital that we make GLP-1s as effective and safe as possible so that more people can reap the benefits and avoid side effects.
By looking at GLP-1 response holistically, instead of individual findings, it’s clear that there are four main profiles, or phenotypes, that GLP-1 users fall into. For example, individuals who struggle to feel satiated regardless of how much they eat may benefit more from non-GLP-1 drug therapies like phentermine-topiramate, while GLP-1s are most effective at driving weight loss in individuals whose bodies digest food too quickly.
Genetic testing can help determine which phenotype (or combination) is causing a person’s obesity and can reduce feelings of stigma and lead to better weight management. However, not all genetic tests are created equal. While some genetic tests can cover thousands of gene variants, multiple causes of obesity, and provide clinically validated drug treatment recommendations, other recently developed tests analyze smaller pools of genetic markers and offer more simplistic, at-home weight loss guidance. Unfortunately, these more streamlined tests don’t provide individuals with the full picture of how weight relates to genetics, nor do they offer clinicians insight into treatment pathways.
Conclusion
The recent attention on precision obesity medicine is important because it helps drive awareness of the underlying causes of obesity and the need for a more individualized approach. However, science has shown us that obesity is a complex condition that isn’t governed by a single gene or even a handful of variants. Instead, it’s a complex web of interconnected biological factors that we can only understand by looking at the bigger picture.
Photo: carloscastilla, Getty Images
Mark Bagnall currently serves as CEO of Phenomix Sciences, Inc. Mark is an entrepreneur and business manager in the healthcare industry. He has held roles as CEO, COO and CFO during his career and has served on the boards of several public and private biotechnology companies. In the past 6 years, Mark has co-founded three start-ups and has advised and invested in several others.
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