Injectable GLP-1 drugs have been a game-changer for many obese patients. But as researchers discover why the drug is ineffective for others, they’re gaining insight into the complexity of the condition.

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Tatyana Volkava/Getty Images

Anna Olson’s first concept of herself was shaped by obesity. That’s when she looked at the photo and thought, “Oh, I don’t look like the other kids.”

Olson’s obesity started in early childhood and ran in her family, leaving her with chronic hunger. Dozens of diets, medications, and exercise regimens were ineffective, and the advice from doctors was always the same. “Eat less.” “And I’m like, ‘Well, this is what I’m doing now. What else can I do?'” she says, and the answer was also, “Well, I just have to eat less.”

In fact, science now shows that obesity is much more complex, with numerous genetic, biological, neurological, lifestyle, metabolic, and behavioral factors contributing to obesity.

Root causes vary

Doctors, patients, and pharmaceutical companies have learned a lot more about obesity and what works and what doesn’t in recent years, since a new class of obesity drugs known as GLP-1 drugs came onto the market. Although obesity manifests itself in one direction: excess weight, doctors say there are probably dozens of different forms of obesity. Therefore, for treatment to be effective, each person’s root cause must be identified and addressed. Obesity doctors and researchers predict that within a few years, treatments will become more tailored to each patient’s needs.

In Olson’s case, genetic testing revealed that she had several genetic and hormonal factors that likely messed up her hunger and satiety sensors. One GLP-1 drug, Ozempic, was temporarily effective, but another drug, Zepbound, proved to be better at rebalancing Olson’s hormones. It was the first time she started addressing specific causes of obesity. Olson started losing a lot of weight, currently weighing 65 pounds as he continues to take medication. “I was able to keep it in check,” she says.

Is a popular drug a precursor to precision medicine?

The use of GLP-1 drugs is already vast, but they will become even more common as drugs become cheaper and more varied, including some recently introduced., Novo Nordisk’s Wegovy tablets are now even easier to use.

Ozempic and Wegovy are brand names for a drug called semaglutide. Zepbound and Mounjaro are brands of a drug called tirzepatide. Both GLP-1 agonists and tirzepatide blocks An additional hormone known as GIP.

Within a few years, doctors say they will also have more ways to determine a person’s specific obesity factors, allowing them to more precisely target the root causes of obesity, much like chemotherapy targets specific cancer subtypes.

The complex structure of obesity may also explain why GLP-1 does not work for many people. a significant minority experience side effects Like nausea. the study Researchers have shown that a significant proportion of patients lose less than 5% of their weight with the drug, but may experience other metabolic improvements.

obesity subtypes

“There are many types of obesity, and each type of obesity has its own unique genetic predisposition.” Andres Acostaa gastroenterologist and hepatologist at Mayo Clinic. Acosta said early research shows that genetic markers could be measured to predict whether a person is likely to respond poorly to GLP-1 drugs, for example.

Acosta is also the co-founder of Phenomics Sciences, a company that sells genetic tests through some clinics. The test is Not covered by insurance.

Cheek swab genetic tests classify people into four basic types of obesity Phenotype (meaning observable traits): Hungry Gut, Hungry Brain, Emotional Hunger, and Slow Burn. (A person may belong to more than one of these groups.) Each category has different hormonal or lifestyle factors that cause obesity. For example, people with emotionally driven eating habits may not benefit as much from GLP-1 drugs.

Professor Acosta also said that while people with gut hormone abnormalities tend to lose more weight with GLP-1 drugs, some people with the ‘hungry brain’ gene marker may have disrupted neural pathways, meaning that the drugs may not be as effective in that group. Older-generation weight-loss drugs, or a combination of new and older drugs, are often most effective for these people, Acosta said.

A viable treatment plan

Anna Olsson says this kind of personalization was key. Genetic testing revealed her phenotype to be “starved brain.” She also found out that she had Bardet-Biedl syndromeshe has a genetic disorder that makes her prone to overeating. Knowing that, she says, reduced the stigma and helped her find the combination of medications that worked best for her.

Now 36, she says her cholesterol and blood sugar levels have improved and she’s closer to her dream of traveling further from her hometown of Minneapolis. “When I was heavier than I am now, I would never have been able to do that.”

It will still be several years before we can more accurately diagnose certain forms of obesity. Dr. Lydia Alexanderformer president Obesity Medical Society. But researchers are getting closer to understanding the variables that drive change.

The chemistry of a person’s gut microbiome, their propensity for addiction, and the molecular shape of their hormone receptors can all influence a drug’s effectiveness, she says. “Drugs may break down faster in some people than others,” she says, which may also explain the difference in response to GLP-1.

In all cases, lifestyle adaptations are important for a complete and lasting response, Alexander said. in fact, Recent review of 37 studies on weight loss It has been shown that people who are dependent on GLP-1 drugs tend to regain weight at a faster rate when they stop treatment compared to those who are dependent on behavioral changes.

Chance of success is 50/50

On the other hand, one of the disadvantages is that popularized GLP-1 drugs He says that means people have higher expectations for rapid weight loss. Dr. Jennifer Mann Galera metabolic disease expert at Harvard University. she says About half of people taking GLP-1 drugs experience a 15% reduction And, “The potential of those drugs is incredible for that half, so everyone who takes those drugs thinks they’re going to be among the half that has that experience.”

Mannegerer says it’s often forgotten that obesity is a chronic, lifelong condition. “No one tool works for each person, and often one tool is not enough to control or reduce the health effects of a condition over a person’s lifetime,” she says. But in the coming years, she says, at least we’ll have more tools to provide better treatment.