The landscape of metabolic medicine is undergoing a seismic shift as glucagon-like peptide-1 (GLP-1) receptor agonists and dual agonists redefine the treatment of type 2 diabetes and obesity. However, new research presented at the ENDO 2026 annual meeting suggests that the real-world application of these therapies is far more intermittent than clinical trials initially indicated. A comprehensive analysis of U.S. insurance claims data and national health programs reveals a complex pattern of "start-and-stop" usage, influenced by drug type, prescribing physician specialty, and socioeconomic factors. While these medications offer profound benefits for blood glucose control and weight loss, the study highlights a significant adherence gap, with approximately 60% of patients discontinuing treatment within two years, though many eventually return to the therapy.
The findings, presented by Sainikhil Sontha, M.S., a research associate at the Boston University School of Public Health, and supported by complementary research from Sajana Maharjan, MD, of HSHS St. John’s Hospital, provide a sobering look at the challenges of long-term weight and diabetes management. As these medications become more prevalent, understanding why patients stop and start treatment is critical for clinicians aiming to prevent long-term complications such as cardiovascular disease and renal failure.
Chronology and Scope of the Retrospective Analysis
The research utilized an extensive retrospective cohort study design, drawing from the Komodo Health U.S. claims database. The study period spanned from January 2019 to June 2025, capturing the period during which GLP-1 medications moved from niche diabetic treatments to mainstream blockbuster drugs. The researchers focused on a specific demographic: adults aged 18 to 64 with a Body Mass Index (BMI) of 25 kg/m² or higher and a confirmed diagnosis of type 2 diabetes.
To ensure the validity of the data, the cohort was limited to patients who had been enrolled in their insurance plans for at least one year prior to starting a GLP-1 medication and who had at least six months of follow-up data available. The medications analyzed included the older generation liraglutide (Victoza/Saxenda), the widely popular semaglutide (Ozempic/Wegovy), and the newer dual-agonist tirzepatide (Mounjaro/Zepbound).
Discontinuation was strictly defined as a gap of more than 60 days in filling a prescription. Conversely, reinitiation was defined as a patient obtaining a new fill after such a gap had occurred. This methodology allowed researchers to track the "persistence" of the medication use over a multi-year period, providing a clearer picture of patient behavior than short-term clinical observations.
The Adherence Paradox: Discontinuation vs. Reinitiation
The core findings of the study underscore a high rate of attrition. According to the data derived from more than 60,000 Americans, 40% of patients discontinued their GLP-1 medication within the first 12 months of starting therapy. By the end of the second year, that number climbed to nearly 60%. These figures suggest that more than half of the patients who start these high-cost, high-impact medications are unable or unwilling to maintain consistent use over the long term.
However, the researchers also identified a trend they characterized as "encouraging." The data showed that discontinuation is often not permanent. Among those who stopped their medication, 41.5% restarted therapy within a year. By the two-year mark, 58% of those who had previously discontinued had reinitiated treatment.
"This suggests that for many patients, these medications aren’t being abandoned permanently; use is more start-and-stop than most people assumed," Sontha noted during his presentation. This cyclical pattern of use suggests that while patients may struggle with side effects, costs, or supply chain issues, the perceived benefit of the drugs often drives them to return to the treatment once barriers are removed.
Factors Influencing Treatment Persistence
The study employed Cox proportional hazards models to identify which factors most strongly predicted whether a patient would stay on their medication or drop out. Several key variables emerged, ranging from the type of drug prescribed to the patient’s socioeconomic status.
The Impact of Drug Generation
One of the most significant predictors of adherence was the specific medication being used. Patients taking newer medications showed much higher persistence rates than those on older versions. Specifically:
- Tirzepatide: Users were 41% less likely to discontinue treatment compared to those taking liraglutide.
- Semaglutide: Users were 28% less likely to discontinue compared to the liraglutide group.
This disparity is likely due to both the increased efficacy of newer drugs and more convenient dosing schedules, such as once-weekly injections compared to the daily injections required for older GLP-1s.
The Role of Specialist Care
The research also highlighted the importance of the prescribing physician. Patients whose first GLP-1 prescription was written by an endocrinologist were 10% less likely to stop the medication compared to those managed by primary care physicians or other specialists. This suggests that the specialized support, education, and follow-up care provided by endocrinologists may play a vital role in helping patients manage the transition to these complex medications.
Socioeconomic and Demographic Disparities
The study revealed troubling disparities in medication persistence. Patients enrolled in Medicaid or Medicare were significantly more likely to discontinue treatment within the first year. Additionally, Black patients faced higher rates of discontinuation than other demographic groups. These findings point to systemic barriers, including the high cost of the medications, insurance coverage "hoops" such as prior authorizations, and potential inequities in patient education and support.
Clinical Side Effects
Unsurprisingly, physical tolerance played a major role in adherence. Approximately 37% of patients who discontinued cited nausea or other gastrointestinal issues. While these side effects are well-documented, the study suggests they remain a primary hurdle for nearly four in ten patients, highlighting the need for better titration strategies and supportive care.
The Physical Activity Paradox
In a parallel analysis presented at the same conference, Sajana Maharjan, MD, explored the behavioral changes associated with GLP-1 use. Using data from the National Institutes of Health’s All of Us Research Program, Maharjan found a surprising trend: patients who lost weight on GLP-1 medications tended to log fewer daily steps than they did prior to treatment.
This finding challenges the traditional "virtuous cycle" assumption that weight loss naturally leads to increased physical activity. While the medications are highly effective at reducing caloric intake and body mass, they may also be associated with a decrease in spontaneous physical activity or "NEAT" (non-exercise activity thermogenesis). This underscores the importance of clinical guidance that emphasizes exercise and strength training alongside medication to prevent the loss of muscle mass and maintain metabolic health.
Clinical and Public Health Implications
The implications of high discontinuation rates are profound. GLP-1 medications are not merely weight-loss tools; they are powerful agents for reducing the risk of major adverse cardiovascular events (MACE), slowing the progression of chronic kidney disease, and managing blood glucose in type 2 diabetics.
"Consistent use of these medications is what produces their protective effects," Sontha emphasized. "Stopping early may mean missed opportunities to prevent heart attacks, kidney disease progression, and other complications."
From a public health perspective, the "start-and-stop" nature of GLP-1 use suggests that the healthcare system is not currently equipped to support patients through the long-term journey of metabolic management. When patients cycle on and off these drugs, they may experience "weight cycling," which some studies suggest can be more taxing on the cardiovascular system than maintaining a higher, stable weight. Furthermore, the economic cost of reinitiating therapy—often requiring new titrations and additional physician visits—adds a burden to an already strained healthcare infrastructure.
Analysis of the Evolving Treatment Landscape
As the medical community moves toward 2026 and beyond, the focus is shifting from the sheer efficacy of GLP-1s to their "real-world" durability. The data from the Komodo Health claims analysis suggests that the initial "honeymoon phase" of these drugs is being replaced by the reality of long-term maintenance challenges.
The findings provide a roadmap for several key stakeholders:
- Insurers and Policymakers: The high discontinuation rates among Medicaid and Medicare recipients suggest that financial barriers and administrative burdens are preventing the most vulnerable populations from receiving the full protective benefits of these drugs. Policy adjustments to lower out-of-pocket costs and streamline renewals could improve long-term outcomes.
- Pharmaceutical Manufacturers: The higher adherence rates for tirzepatide and semaglutide compared to liraglutide indicate that ease of use and higher potency are key to patient retention. Future drug development should continue to focus on minimizing gastrointestinal side effects and extending dosing intervals.
- Clinicians: The "endocrinologist advantage" suggests that more intensive patient education and specialized management are necessary. Primary care providers, who handle the bulk of GLP-1 prescriptions, may need more resources to mimic the support structures found in specialized endocrine clinics.
The research presented at ENDO 2026 serves as a critical reminder that while medical science has provided a powerful tool for combating the twin epidemics of diabetes and obesity, the human element—access, side effects, and behavioral changes—remains the final frontier in achieving lasting health improvements. The goal for the next decade of metabolic care will not just be getting patients onto these medications, but providing the comprehensive support necessary to keep them there.
