Many Patients Quit Taking GLP-1 Drugs: Understanding Why Is Key

Weight regain and worsening cardiometabolic status are real threats. Too few physicians pay notice, a new viewpoint argues.

In addition to ensuring equitable access to the glucagon-like peptide-1 (GLP-1) receptor agonists, the medical community needs to figure out how to keep patients on the drugs long term to fully realize their benefits, researchers highlight in a JAMA viewpoint.

In recent years, interest in these medications—initially developed to treat type 2 diabetes—has exploded, primarily because of their weight-loss effects but also due to their cardiovascular benefits, as seen in the SELECT trial. There are, however, estimates that 50% to 75% of patients stop treatment within a year, leading to a rebound in body weight in many cases, the loss of other benefits, and a potential worsening of cardiometabolic measures.

That hasn’t been discussed enough, Sadiya Khan, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), lead author of the viewpoint, told TCTMD.

“We don’t have a clear sense of why people are stopping, who’s stopping, and how we can help support people to stay on these highly effective medications,” she said.

Though there are multiple possible reasons that people may discontinue treatment with GLP-1 receptor agonists, high out-of-pocket costs and side effects appear to be among the leading culprits.

But a lack of appropriate framing around use of these medications as chronic therapies—and not short-term fixes—may also be contributing, Khan suggested. “I do think there needs to be a good discussion around this—there’s a lot of short-term benefit that can happen, but it’s not sustainable without ongoing use.”

Research, Clinical, and Policy Implications

Discontinuation is a common issue for many chronic therapies, but it’s “particularly problematic” for GLP-1 drugs—such as semaglutide (Ozempic, Wegovy, and Rybelsus; Novo Nordisk) and tirzepatide (Mounjaro and Zepbound; Eli Lilly), a dual GLP-1/glucose-dependent insulinotropic peptide (GIP) agonist. That’s because of their high cost, the large population potentially eligible for treatment, and the possibility of worsening cardiovascular risk once they’re stopped, Khan et al say. They put a spotlight on this by reviewing the implications at various levels.

From the research standpoint, there is a need to understand the barriers to long-term adherence, whether that’s related to cost, the injectable nature of the therapy, supply issues, or other factors, and how to overcome them, Khan said. Moreover, she and her colleagues note, “quantifying whether short-term therapy results in some enduring benefit, a return to pretreatment cardiovascular risk, or rebound risk in excess of baseline risk should be a priority.”

The answers to those questions might help at the clinical and health-system levels, where physicians and others are having discussions with patients considering use of GLP-1 receptor agonists. There, Khan said, “the decision to start these medications should be framed in that long-term chronic perspective to make sure that that planning is in place and that there is a strategy to help support patients once started to maintain their use so that they can maintain the benefit.”

Such strategies should be coupled with efforts to ensure equitable access to the medications in the first place, the authors say.

We don’t have a clear sense of why people are stopping, who’s stopping, and how we can help support people to stay on these highly effective medications.Sadiya Khan

At the policy level, Khan et al highlighted issues around high out-of-pocket costs, restrictions placed on the use of GLP-1 receptor agonists by insurers, discrepancies in how the drugs are priced in the US versus elsewhere, and ongoing drug shortages, which impede access.

Though uptake of these medications likely will continue to grow in the coming years, “the staggeringly high discontinuation rates . . . should raise alarms for clinicians, policymakers, and public health experts,” the authors stress. “The current emphasis on equitable initiation is a necessary first step, but it is insufficient. There is a strong ethical and economic case to identify and implement strategies to improve long-term persistence of GLP-1 receptor agonist use to promote optimal population health outcomes in the long run.”

Eyeing Future Approaches to GLP-1s

Commenting for TCTMD, Michael Blaha, MD (Johns Hopkins Medicine, Baltimore, MD), acknowledged that discontinuation of treatment remains a current challenge for GLP-1 receptor agonists, with structural factors, pricing, insurance coverage, and other factors coming into play. But he said that speaks to an even larger question: what will GLP-1 receptor agonist treatment look like in the future?

There’s no doubt that this isn’t something that you can take for a short period of time and then stop.Michael Blaha

It's clear that when patients stop GLP-1s early on, much of the weight that was lost is regained, Blaha said. “So there’s no doubt that this isn’t something that you can take for a short period of time and then stop.”

But in the future, it will be interesting to explore whether there are some patients in whom therapy can be dialed back either in terms of frequency or dose in conjunction with lifestyle changes, he said. In addition, in the coming years, oral GLP-1 receptor agonists and injectable formulations that require less-frequent dosing—monthly perhaps—may become available, which could change considerations around use of the medications.

Some element of lifestyle modification will be key, however, Blaha said. “Some people out there say, ‘Well, gosh, the GLP-1s are just covering up our lifestyle problem. They’re not really the solution. And I don’t necessarily agree with that, but I definitely agree that the solution is some combination of lifestyle and GLP-1.”

While research in those areas is developing, a critical aspect of keeping patients on GLP-1 receptor agonists over the longer term is having up-front conversations with patients about what they can expect and how important it is to stick with their treatment regimens moving forward, Blaha said, adding that “this is a conversation that doesn’t happen enough, particularly in this weight-loss space.”

Structural factors influence adherence, Blaha said, “but there’s also more clear communication that needs to happen between patients and their physicians about the actual plan.”

There are a lot of challenges with adherence for these medications, Khan said, underscoring the importance of “going into the prescribing of [them] with a lot of anticipatory guidance and counseling for barriers that may preclude someone from being able to stay on it long term, and [highlighting that] the benefits are really only while on the therapy, it appears.”