Placebo at Piazza Sordello, Mantova

Weight Regain in the Real World vs a Placebo-Controlled Trial

It created quite a stir last week when Epic Research published an analysis suggesting that weight regain in the real world does not look the same as a placebo-controlled trial. After all, regain is quite an important subject.

Obesity is clearly a chronic disease, requiring chronic care. But lots of people try to avoid this fundamental truth. They imagine that they or others should be able to lose weight and then go back to their prior lives, vowing to be careful not to gain weight again.

So when an analysis comes along to say that weight regain is not the immediate consequence of discontinuing a GLP-1 medicine, it’s quite natural for obesity experts to think there’s “something fishy here.”

The Unreal World of a Placebo-Controlled Trial

A placebo-controlled trial is absolutely essential for understanding the effects of a medicine in treating a disease. It is the placebo-controlled trials that tell us a GLP-1 agonist like semaglutide or tirzepatide can be highly effective for obesity. It is also  placebo-controlled trials (like this, this, and this) that tell us if you start getting a placebo in place of a GLP-1, absent any other interventions, weight regain is inevitable.

So What’s Up with the Real World Data from EMRs?

This is not the story told by the data from Epic Research, based upon analysis of electronic medical records (EMRs) for people who lost weight with a GLP-1. The analysis looked at what happened to the weight of people who took either liraglutide or semaglutide and lost some weight, but then stopped taking the drug. Researchers found that many people did not regain weight in the first year after stopping the drug.

Obesity medicine physician Katherine Saunders offers two reasons for caution in looking at this EMR analysis. First of all, she cautions that “Epic EMR queries are tricky.” So it’s quite easy to get a false or misleading readout.

She goes on to say this analysis give her no reason to doubt a fundamental truth of obesity care:

“Our experience is that regain happens after stopping a GLP-1 – sometimes right away and sometimes it takes a little while. But I can’t think of patients who stopped a GLP-1 and didn’t experience some extent of regain.

“So I wouldn’t start a patient on a GLP-1 for weight management unless they were prepared to continue medical obesity treatment long-term – not necessarily the same medication, but some kind of medical treatment.”

The Whole Truth of the Real World

None of this tells us to simply reject the analysis of weight regain in EMRs. The whole truth of what goes on in the messiness of the real world is worth pursuing. The analysis from Epic Research, at best, gives us only a tiny sliver of that truth. It only looks at one year. We have no insight about the reasons for stopping. The data tell us nothing about what else people did after their initial trial of a GLP-1. Maybe they took other obesity meds. Maybe they had metabolic surgery. The possibilities are many.

It seems quite possible that, after going to all the trouble to seek out treatment with a GLP-1, they followed through with other strategies for obesity treatment.

Thus, the best response to this EMR analysis is not to reject it, but to recognize its limitations for informing us about the whole truth of real world experiences with GLP-1 obesity medicines. It raises more questions than it answers.

Physicist and philosopher Hermann von Helmholtz admonished scholars to be “more fearless of the consequences of the whole truth than any other people.” Fearlessly pursuing the whole truth on this subject is an excellent idea.

Click here for the EMR analysis, here and here for further perspective.

Placebo at Piazza Sordello, Mantova; photograph by Dennis Radaelli, licensed under CC BY-SA 4.0

Subscribe by email to follow the accumulating evidence and observations that shape our view of health, obesity, and policy.


January 30, 2024