People trying to lose weight often count calories, carbs, steps and reps and watch the scales. Soon, they may have another number to consider: a genetic score indicating how many calories a person needs to feel full during a meal.
This score may help predict whether someone will lose more weight on the drugs liraglutide or phentermine-topiramate, researchers report June 6 in Cell Metabolism. A separate study, posted to medRXiv.org in November, suggests that individuals with a higher genetic propensity for obesity benefit less from semaglutide compared to those with a lower genetic predisposition.
Such genetic tests may one day help doctors and patients select personalized weight-loss treatments, some researchers say. But the genetic scores “are not perfect predictors of drug response,” says Paul Franks, a genetic epidemiologist at Queen Mary University of London who was not involved in either study. “They show a tendency.”
For the Cell Metabolism study, Mayo Clinic researchers measured how many calories it took for about 700 adults with obesity to feel full when given an all-you-can-eat meal of lasagna, pudding and milk. The calorie intake varied widely, ranging from about 140 to 2,200 calories, with men generally needing more than women. The team used machine learning to compile a genetic score based on variants of 10 genes associated with obesity. That score is designed to reflect the calories people required to feel full.
Then, the Mayo team and colleagues from Phenomix Sciences Inc, headquartered in Menlo Park, Calif., conducted two clinical trials.
In one 16-week trial, people with obesity received either a placebo or liraglutide — a GLP-1 drug branded as Saxenda. GLP-1s are a class of diabetes drugs that have shown promise with weight loss. People with a lower genetic score lost more weight on liraglutide than those with higher genetic scores.
Conversely, in a yearlong study comparing a placebo with phentermine-topiramate — a combination of a stimulant and an anti-epileptic medication sold under the brand name Qsymia — those with a high genetic score lost the most weight on that drug .
The researchers already had data suggesting a link between satiation and phentermine-topiramate response, says Andres Acosta, an obesity expert at Mayo. But, he says, they were not expecting that patients who needed relatively few calories to feel full would respond best to a GLP-1 drug like liraglutide.
“We think,” Acosta says, “that there’s going to be a strong genetic disposition that explains how we eat and when we like to eat” — and which weight loss drug may work best for a given person. Having a genetic test to guide obesity treatments could “change the conversation forever,” he says. “You’re not trying this because you saw a commercial about it or an ad … You will try it because of your confidence that this is the best thing for your biology.”
But genetics are not the sole predicters of drug responses, says Elizabeth Cirulli, associate director of research at the genetic testing company Helix in San Diego.
As with the Mayo Clinic study, Cirulli and colleagues at Helix tested a genetic score’s ability to predict response to a GLP-1 drug — this time semaglutide, which is sold as Ozempic and Wegovy. Helix’s genetic score measures obesity risk and encompasses thousands of genetic variants. While the score correlated with who was likely to lose weight on semaglutide, nongenetic factors also played a big role, Cirulli says.
For instance, in Helix’s study, people who were male, had type 2 diabetes, high blood pressure, sleep apnea or nonalcoholic fatty liver disease lost a little less weight on semaglutide than women or those without those health problems. In people with type 2 diabetes, higher hemoglobin A1c levels — a record of blood sugar levels over two to three months — were associated with less weight loss.
The Mayo study also found that women tended to lose more weight on liraglutide than men. Age and starting weight were also predictors of who would benefit from the tested drugs.
“I wonder if it’s actually just more about this drug working better in a certain type of person, as opposed to it actually being about the genetic differences,” Cirulli says.
Franks agrees. The Mayo study was small and didn’t seem to account for some confounding factors. “The statistics are a bit wobbly,” he says. It could be true that the amount a person needs to eat to feel full may be an important predictor of which weight loss drug they’ll do better on. “But whether the genetic score is quite as valid as they imply it is, I’m not sure.”
Still, some patients are already trying the test to help them select obesity treatments.
“I’ve been pretty much overweight my entire life,” says Anna Olsen, from Minneapolis. She’s tried nearly every weight-loss tactic in the book, including GLP-1 drugs. But she had never considered taking a genetic test to see what strategy she should try next. “You never really think about genetic testing, because everybody thinks if you’re overweight, it’s your own fault,” Olsen says. When an obesity specialist recommended MyPhenome, the test Phenomix Sciences licensed from Mayo, Olsen was game.
The test indicated that Olsen has a high genetic score, what the company calls a “hungry brain.” That makes sense, she says. “I could have a plate in front of me, and I could eat it, and I could feel full, but my brain would still be telling me it’s time to keep eating.” As a result of the test, her doctor put her on phentermine-topiramate. Now, Olsen says, “it’s so weird. It’s like my brain is quiet for the first time in years … I can stop myself from eating everything because I know that I’m full.”
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