Article By Sumathi Reddy
Original article here: https://www.wsj.com/health/pharma/ozempic-weight-loss-drug-ineffective-why-6d7059bb
April 1, 2024
Behind the blockbuster success of drugs like Ozempic and Wegovy is a less-noticed phenomenon: Some people don’t lose much weight on them.
There is wide variation in weight loss on these types of drugs, called GLP-1s. Doctors say roughly 10% to 15% of people who try them are “non-responders,” typically defined as those who lose less than 5% of their body weight. These patients, doctors say, don’t experience enough appetite reduction to result in significant weight loss.
Researchers are studying why some people drop a lot of weight on them while others lose little. The answers might yield broader clues about weight loss and provide more insight into these medications, which have transformed the way Americans lose weight.
Doctors believe some people might be resistant to the drugs as a result of genetic differences. Other possible reasons could include certain medical conditions and medications, how much weight a person lost before taking the drugs, and differences in how people metabolize them.
Wide range of weight loss
In a trial for the drug semaglutide—marketed as Wegovy and Ozempic—about 14% of patients lost less than 5% of their body weight. About a third lost less than 10%. In a trial for tirzepatide, sold as Mounjaro and Zepbound, 9% of people lost less than 5% of their body weight and 16% lost less than 10%.
Even among those who lost weight, amounts ranged from around 5% to upward of 20%.
“There’s going to be extreme variability in how people respond,” says Dr. Eduardo Grunvald, an obesity-medicine physician at UC San Diego Health.
Anthony Esposito, a 68-year-old in Austin, Texas, whose body-mass index puts him in the overweight category, wanted to take a GLP-1 drug to lose about 10 pounds. He stopped Wegovy after a month because it made him feel sick, and then tried Ozempic for about six weeks. Esposito says that he didn’t lose a pound and that his appetite remained the same.
“It did not budge the needle,” he says.
For other people, initial success fizzles. Melissa Traeger, a 40-year-old in Nashville, Tenn., started off at nearly 300 pounds and lost about 10 in the first six weeks. Then the weight loss stalled. She shed another few pounds in the next couple of months, leveling off at 285.
“There was appetite suppression the first one-and-half months but it’s kind of just fallen off after that,” she says. Traeger plans on switching to another GLP-1 medication.
Novo Nordisk, which makes Ozempic for Type 2 diabetes and Wegovy for obesity, says that not all patients will respond to all therapies, and notes that the overwhelming majority of patients treated with Wegovy lost some weight in the semaglutide trial. Eli Lilly, which markets Mounjaro for diabetes and Zepbound for obesity, says that obesity is a heterogeneous disease and that most people in its clinical studies achieved at least a 20% weight loss at the highest dose.
Why results vary
Obesity in some people might be driven by something besides the hormones that weight-loss drugs mimic to suppress appetite, says Grunvald. In those cases, the drugs probably won’t make much of a difference.
People who have had obesity their whole lives might have genetic mutations preventing them from responding strongly to the drugs, says Dr. Steven Heymsfield, a professor who studies obesity at Louisiana State University’s Pennington Biomedical Research Center. And people who metabolize the drugs quickly might not experience as much of an effect, he says.
Other medical issues could dampen the effect of weight-loss drugs. People with Type 2 diabetes typically lose less than those without the condition, Grunvald says.
Diet and exercise habits before starting the drugs can influence how much weight one loses. People who have already shed a lot of weight through lifestyle changes might not drop much more on the drugs, Grunvald says.
Other medications can play a role, too. Many drugs—such as certain types of antidepressants and antipsychotics—have weight gain as a side effect.
“You could have some other drug interactions that prevent the effect of the GLP-1 drugs from working,” says Heymsfield.
If the drugs don’t work
When people don’t respond to a GLP-1, Grunvald says he looks to see if there is room for improvement in diet and exercise. Then he will suggest trying a different drug in the same class, or adding other medications, such as an older weight-loss drug. Physicians will also discuss bariatric surgery with patients who meet the criteria.
Doctors typically have patients try the new drugs for three to six months and increase the dose each month to see if patients respond.
Dr. Gitanjali Srivastava, an associate professor and co-director at the Vanderbilt Weight Loss Center, says she had a patient who tried multiple GLP-1 medications and none worked. The patient did respond to one of the older weight-loss medications that typically don’t result in as much weight loss.
Genetic testing can yield clues for patients who have had obesity since childhood and are entirely resistant to even the highest doses of Mounjaro, says Dr. Myra Ahmad, chief executive of Mochi, a telehealth obesity clinic. If they test positive for certain genes, they can try a medication for genetically linked obesity, she says.
Battling frustration
Even when people don’t lose weight on the GLP-1 drugs, they might be improving health in other ways, such as lowering blood-sugar levels and helping to manage diabetes.
“Considering ‘response’ solely in terms of weight loss, and not broader outcomes for health and quality of life, overlooks many of the benefits seen with treating obesity beyond weight loss,” says Dr. Jaime Almandoz, medical director of the Weight Wellness Program and associate professor of internal medicine at UT Southwestern in Dallas.
Still, for people who have been hoping the new drugs will be a panacea, not losing weight on them can be frustrating.
Some have been struggling with weight for years, and might have already tried bariatric surgery or older medications. “Yet another option not working can feel very demoralizing,” says Ahmad.
Write to Sumathi Reddy at Sumathi.Reddy@wsj.com
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