While drug developers work to mitigate the side effects associated with GLP-1–based obesity drugs, recent studies reveal that myriad variables are causing patients to stop treatment.
When GLP-1 drugs recently became a trendy talking point for their impressive weight loss efficacy, their less-than-appealing aspects also came into focus, particularly gastrointestinal side effects.
Nausea, vomiting, diarrhea, constipation and abdominal pain are all commonly reported by people dropping pounds with Novo Nordisk’s Wegovy (semaglutide) and Eli Lilly’s Zepbound (tirzepatide). In fact, real world studies indicate these GI adverse events develop in between 40-70% of GLP-1 treated patients.
With discontinuation rates a concern for companies, drug developers and practitioners are working together to help patients manage the worst of these side effects so they can stay on drug and benefit from the significant weight loss generated by the popular injectables.
In a recent survey of 50 physicians conducted by strategic advisory firm DNB Markets and Back Bay Life Science Advisors, 94% of doctors ranked the benefit-safety profile as one of the most important factors in prescribing a weight loss medication.
Physicians seem to be clamoring for drugs with fewer side effects, Peter Bak, partner and managing director of Back Bay Life Science Advisors, told BioSpace last month. Careful titration or dose adjustments, updated or combination formulations, and drugs targeting side effects are all strategies being deployed to improve the palatability of GLP-1s.
For David Cummings, director of the weight management program for VA Puget Sound Health Care System, side effects are less of a deciding factor. “For my patients, [the gastrointestinal side effects] are not a huge deal, but it’s not a trivial deal either,” he told BioSpace.
Titration, Combinations and Secondary Drugs
Side effects like nausea and constipation are “easy to understand” as they relate to the drug’s mechanism of action, Cummings explained. One of the ways in which GLP-1s make patients feel full is by slowing GI motility. If the drug has too great an effect in the upper GI system, it can cause nausea, as happens when eating a huge meal too fast. If the drug has too strong an effect in the lower intestine, slow GI motility leads to constipation, he said.
“In both cases, that’s just the drug doing what it’s supposed to do,” and the proper response is to decrease the dose to a level that is still efficacious but with fewer side effects, Cummings said. Interestingly, he said researchers are uncertain why diarrhea occurs with GLP-1 treatment.
A key strategy being deployed by drug developers to improve side effect profiles is titration. The starting dose and length of time to maintenance dose are critical to optimizing patient tolerability, Blai Coll, chief medical officer of Structure Therapeutics, told BioSpace.
Another popular approach is combination formulas. The addition of a gastric inhibitory polypeptide (GIP)—such as in Zepbound’s formulation—or an amylin receptor agonist can mitigate the gastrointestinal effects driven by the GLP-1, Coll said.
Amylin has become a hot mechanism for weight loss drug developers as companies like Novo, Structure, AstraZeneca and Viking Therapeutics chase after approval of their candidates.
Still other companies aim to target GLP-1-associated side effects with a separate, secondary drug.
In January, Jaguar Health subsidiary Napo Pharmaceuticals filed a patent application for Mytesi to treat the GI side effects common with GLP-1 and GIP treatments used for obesity.
Mytesi is a plant-based oral drug already approved for HIV-related diarrhea that has shown additional benefits for abdominal pain, discomfort, bloating and constipation when studied in HIV, irritable bowel syndrome (IBS) and cancer therapy-related diarrhea.
While Cummings isn’t familiar with Mytesi in particular, he said that if the drug truly helped to treat GLP-1 side effects, “I’d certainly consider using it.”
Ben Urick, senior director of health outcomes at Prime Therapeutics, isn’t convinced, however. He told BioSpace that the clinical goal is usually to instead find an alternative treatment with less burdensome side effects.
“You’d have to really convince me that we would need another drug,” said Urick, a pharmacist. For a patient with dire disease circumstances and no other option, it may be useful, he added, “but not for your average user.”
GLP-1 Discontinuation Is Multifactorial
Despite these extensive efforts, the jury is still out on just how much of a problem GLP-1–associated side effects are. Cummings noted that only about 5% of his patients on GLP-1 medications have really had problems with side effects.
A series of real-world studies mirror this assertion, with a 5% discontinuation rate found for patients taking semaglutide over roughly 30 weeks due to adverse events.
Another real-world study, published in July 2024 by Prime Therapeutics, showed that 85% of patients were no longer taking GLP-1 drugs two years after starting treatment. But this isn’t only due to tolerability concerns. Urick said discontinuation can be attributed to five common causes, of which side effects are only one, along with affordability, availability, physician drug switches and the achievement of weight loss goals.
However, “I don’t think shortages have quite as big of an impact as you would think,” Urick said, adding that patients on lower doses of the drugs are more likely to be affected.
Despite literature touting GLP-1s as long-term treatments, prescribers have indicated to Urick that patients often only use the drugs to reach certain weight loss goals and then discontinue treatment once these are accomplished. Another indicator of this phenomenon is that in Prime’s study, patients without type 2 diabetes discontinued treatment at a higher rate than those with the disease.
Urick also noted that Prime’s study data was initiated in 2021 and included older products that are no longer used as often, causing the treatment persistence rate to drop to 15%. With a “more modern product mix” led by heavy hitters like Zepbound and Wegovy, Urick said he expects to see two-year persistence rise to closer to 25%.
That’s not to say that side effects are not an issue for patients. In fact, Urick believes the role of side effects and achieved weight loss goals have been underestimated in efforts to uncover the cause of GLP-1 discontinuation. While this study wasn’t designed to measure it, a further probe into Prime’s data revealed those who persisted on treatment had lower side effect rates than those who discontinued their GLP-1. For Urick, this is a signal that side effects could be associated with stopping a drug early. “There is a relationship between the two,” he said.
Ultimately, Coll said, “I don’t think there’s a silver bullet by which we can continue benefiting from the GLP-1s while completely eliminating all the GI events.” He reiterated an emphasis on combination therapies with GIP and amylin to optimize tolerability. “That’s how we’re looking into the future.”
