Three big unknowns about popular weight-loss drugs

But there is still much we don’t know about these therapeutics, broadly known as GLP-1 agonists. As their popularity surges, here are three important questions that must be answered:

1. Must the drugs be used for a lifetime? Or is there a pathway to stopping?

Drug manufacturers intend for patients to use GLP-1s in perpetuity. Of course, these companies have a financial interest in having people use these drugs for as long as possible, but the argument has scientific merit: If obesity is a chronic ailment like hypertension and diabetes, and patients with those other conditions take medications for a lifetime, then why not treat obesity the same way?

Available data back up the need for indefinite treatment. A 2022 study found that a year after stopping semaglutide, individuals on average regained two-thirds of their prior weight loss. Blood pressure and blood sugar also began reverting to pre-treatment levels.

If lifelong treatment is the standard of care, patients should be aware as they consider starting GLP-1s. This is especially important for young people, who would be committing themselves to using these drugs for decades. Steven B. Heymsfield, a physician and professor of metabolism and body composition at Louisiana State University, told me, “We don’t really know how the body will respond to many, many years on these drugs.” For instance: Does effectiveness lessen over time? Could rare complications increase in frequency?

Heymsfield thinks there could be a path for some people to wean off the drugs. He has seen patients who reduced usage from the recommended once-a-week dose to once every two weeks. “They would gradually regain some weight because that lowers the effective dose,” he said, but they might be able to offset it with lifestyle changes.

This is what happens with hypertension and Type 2 diabetes: Some patients can make sufficient behavioral modifications to eventually stop their medications. Drugmakers might not see it as in their interest to conduct studies on what the proper length of treatment should be, but they should consider that more people might be willing to try these medications if there were a path to reducing their use.

2. Will people take these drugs long enough to realize health benefits?

The rate at which people discontinue these drugs is shockingly high. A recent analysis of insurance company data found that less than 1 in 3 patients who started taking GLP-1s for weight loss were still taking it a year later.

In Heymsfield’s experience, people stop for three main reasons. First, the drug might not be achieving the desired effect. Second, common side effects, such as dizziness, stomach pain, vomiting and diarrhea, could exceed perceived benefits. Third, people might “get tired of the drug’s expense” and stop paying for it once they’ve met their weight-loss goals.

The first two reasons could apply to virtually any therapeutic. The third goes back the concern that most short-term benefits of weight loss would be lost upon cessation. If a large proportion of people stop the drug so quickly, it would become even less cost-effective than it already is. Manufacturers should address reasons for discontinuation as they develop additional obesity treatments.

3. How can inappropriate use be curbed?

It bothers Heymsfield to see celebrities and even people he knows taking the drugs who are “marginally overweight or not very overweight” and “slimming down to extremely low weights.”

“What I worry about more than anything is that there’s a legitimate need for [GLP-1s] and a legitimate population of people who should be on the drugs and monitored professionally,” he said. Reports of adverse effects from people inappropriately prescribed the drug or harmed from taking knockoff versions might deter those who could actually benefit from using them.

The Food and Drug Administration, as well as state boards of medicine and professional societies, must do more to warn against inappropriate prescribing. Federal agencies should also continue to crack down on rogue internet pharmacies and operations that sell unauthorized versions of the drugs.

Heymsfield describes the field of obesity medicine as being “exuberant” over the promise of GLP-1s, though he believes other specialists agree with his calls for caution. The temptation to push for rapid and widespread adoption must be tempered by the reality that major questions remain. It would be a shame if semaglutide, tirzepatide and similar drugs were to end up relegated as overhyped fads rather than the medical breakthroughs they appear to be.