More study needed into the ‘why’ of new weight-loss drugs

Hitting the market over the past six years, the drugs Ozempic, Wegovy and Mounjaro are viewed as a therapeutic breakthrough for the 42% of the U.S. population who are clinically obese. One Seattle endocrinologist suggests, however, that more research is needed.

These drugs are not the be-all and end-all to weight-loss therapy, wrote Dr. Michael Schwartz in a commentary published Oct. 2 in The Journal of Clinical Investigation. His co-author was Sophie Yang Gou, a postdoctoral fellow in Schwartz’s lab at the University of Washington School of Medicine.

Many experts seem to be saying “OK, we’ve fixed this problem. We’re done,” noted Schwartz, who co-directs the UW Medicine Diabetes Institute. That is simply not the case, he said.

Some patients can’t tolerate these drugs’ side effects, which include nausea, pain, depression and gastrointestinal problems.  Perhaps most concerning is that the weight loss induced by these drugs appears to rapidly reverse once they are discontinued. Some patients have reported gaining back more weight than they carried when they started, the authors note.

This underscores the need to understand better how these drugs work and to use this information to guide future drug development, the authors contend. Today, that deep understanding simply does not exist, they wrote. 

Currently, Wegovy is approved by the FDA for the treatment of obesity while Ozempic and Mounjaro are indicated for patients with type 2 diabetes.

All three drugs mimic the action of one or more naturally produced hormones, including glucagon-like peptide-1 (GLP-1). Effects include increased insulin, appetite suppression, and reduced gastric emptying, Thus patients feel full even when they eat less.

Mounjaro also mimics a second, closely related hormone called GIP, which targets receptors for both GIP and GLP-1 and produces a more powerful effect.

The drugs appear to cause weight loss through two distinct actions in the brain, Schwartz explained: They provide a sense of satiety, so patients are less hungry. They also seem to target brain systems that protect against weight loss and which are activated when the brain senses you have lost weight. The latter, called the energy homeostasis system, mounts adaptive responses when weight loss greater than 5% has occurred.

The three drugs appear to inhibit this adaptive response, which allows for much greater weight loss than is achieved with other obesity drugs.

Should a patient stop taking the drugs, however, the adaptive response to weight loss returns, said Schwartz, who has studied the brain’s role in obesity and diabetes for 30 years.

“Once the drug is discontinued, the lost weight is regained at an extraordinary pace, even faster than when it was lost — presumably because the energy homeostasis system, having been suppressed for months, suddenly awakens,” the authors suggest.

“The brain is unaware of the extent of weight loss occurring while it’s on this drug,” Schwartz said. “Once the patient stops taking the drug, the brain, in a sense, wakes up and asks: ‘Wait a minute, what is this? Why is the body weight so low?’”

The adaptive response kicks into high gear and the weight comes back, sometimes dramatically,” he added

“A better understanding of how signals emanating from the GI tract communicate with the energy homeostasis system may enable us to control body weight in a far more specific manner,” Schwartz said.

Drugs modulating the adaptive response to weight loss have important therapeutic potential and in theory, can be developed with much greater specificity than is achieved with the current drugs, he said.

This type of approach might allow lost weight to be maintained with fewer side effects, he said, noting that the approval of these drugs was based on safety information from thousands of people on medication for a period of months.  As millions of people are placed on these drugs for periods of years, however, the potential for unanticipated off-target effects grows, he added.

There are also some ethical and financial questions that need to be addressed, he said. What if a teenager is started on one of these powerful drugs? Are we going to commit them to taking them for the rest of their lives to keep the weight off? Should they? At $1000 a month or more, the high cost is a financial strain for many families, he said, especially if their health insurance does not cover them.

“I think the main point, is we shouldn’t be complacent, and assume that these drugs are the answer to these chronic conditions,” Schwartz said. “We are giving drugs where we don’t understand totally how they work. We have the opportunity to build on what we have learned from these drugs to develop even better options for the future management of obesity and associated metabolic disease.”

Written by Barbara Clements, UW Medicine Newsroom.