Published in Scientific Reports by researchers at the University of California, San Francisco, the observational study analyzed outpatient pharmacy and medical claims. The results build on previous clinical trial data, specifically the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial, which showed a 34% risk reduction. This new research extends those findings to a large, real-world cohort of commercial insurance and Medicare Advantage enrollees.
Semaglutide and COVID-19 Mortality Data
The research team drew data from the Optum Labs Data Warehouse, examining records of 10,109,596 people continuously enrolled between July 1, 2021, and June 30, 2022. The study sample had a mean age of 47 years. The majority of participants were White (62%) and female (51%), with the South being the most commonly represented region at 42%.
Obesity, affecting 15% of the cohort, and type 2 diabetes, affecting 13%, stood as the most prevalent comorbid conditions. Nearly one in ten participants had heart disease. Less than 8% had a history of SARS-CoV-2 infection, and approximately 45% had received at least one dose of a COVID-19 vaccine. The mean Charlson Comorbidity Index, a measure of overall patient disease burden, was 1.12. The study lacked smoking status data for 90% of participants, while 7.7% classified as never smokers and 2.2% as current or former smokers.
Researchers identified semaglutide users by searching pharmacy claims for the brand names Ozempic, Wegovy, and Rybelsus, or the Current Procedural Terminology code J3590. They defined COVID-19-related death using discharge-status codes and an International Classification of Diseases, Tenth Revision (ICD-10) U07.1 code recorded within 30 days before death. They also accounted for other medications that could influence mortality, including systemic corticosteroids, anti-CD20 monoclonal antibodies, and inhibitors of tumor necrosis factor-alpha or interleukin-6.
Despite semaglutide users being older and carrying higher rates of type 2 diabetes, obesity, and heart disease, the adjusted data showed a strong protective association. Among users, researchers recorded 192 COVID-19-related deaths in 96,842 person-years, yielding an incidence rate of 1.98. Non-users saw 13,591 deaths in 8,692,940 person-years, an incidence rate of 1.56. After applying inverse probability treatment weighting and Cox regression models to balance health differences, semaglutide use correlated with a hazard ratio of 0.51 for COVID-19 mortality. The Cox model additionally adjusted for type 2 diabetes and obesity because these factors remained imbalanced after weighting.
How the GLP-1 Receptor Agonist May Work
The exact biological mechanisms driving this lower COVID-19 mortality remain unclear. The study did not directly measure changes in blood glucose, body weight, airway function, or inflammation. However, researchers propose that the GLP-1 receptor agonist may offer protective effects beyond its established role in glucose regulation and obesity treatment.
Potential explanations include anti-inflammatory properties, reduced airway hyperresponsiveness, and the general health improvements associated with weight loss. Because the study identified this mortality association across the overall insured cohort rather than strictly among those with documented SARS-CoV-2 infections, the findings highlight the drug’s broad therapeutic potential. The data also confirmed that type 2 diabetes and obesity independently increased the hazard of COVID-19-related death, aligning with established public health evidence regarding severe viral illness.
What Happens Next
While the 10-million-person sample provides robust observational data, the authors caution that the findings do not establish causation. Unmeasured confounding remains a possibility, though an E-value of 3.31 suggests an unmeasured factor would need strong links to both semaglutide use and COVID-19 mortality to explain the results entirely. Additionally, the claims-based outcome may have missed deaths where COVID-19 was not formally documented.
Moving forward, prospective research and randomized controlled trials are necessary to determine if semaglutide directly reduces COVID-19 mortality. Future investigations should also explore dose-response relationships, optimal treatment duration, and whether the drug lowers mortality from other infectious or inflammatory causes.
The authors emphasize that these findings should not be interpreted as evidence for prescribing semaglutide specifically to prevent COVID-19 death. Extending research beyond commercially insured populations will also be crucial to improve generalizability and real-world relevance for diverse patient groups.
— Aisha Mensah, health desk, AXO News