Semaglutide Linked to Lower COVID-19, Influenza Severity in Study

Adults with documented use of semaglutide before contracting COVID-19 or influenza had significantly lower rates of 30-day mortality, hospitalization, and acute kidney injury compared with those using metformin without prior GLP-1 receptor agonist exposure, according to a retrospective cohort study published in Biology Methods and Protocols.¹ The findings, drawn from a federated US electronic health record network spanning more than 29 million patients, add to observational evidence suggesting GLP-1 receptor agonists may influence the clinical course of respiratory viral infections beyond their established metabolic effects.¹

Real-world analysis of over 29 million patients found lower mortality, hospitalization, and kidney injury with prior semaglutide use

Researchers used an active-comparator design, identifying adults with documented COVID-19 or influenza infection between January 1, 2020, and December 31, 2025, and classifying them by pre-infection exposure to semaglutide (2 or more orders or administrations in the 12 months before infection) versus metformin without any prior GLP-1 receptor agonist or tirzepatide exposure.¹ After 1:1 propensity-score matching on demographics, body mass index, HbA1c, vaccination status, prior infection, antiviral use, comorbidities, and health care utilization, the matched cohorts included 7092 patients per arm for COVID-19 and 1920 patients per arm for influenza.¹ Semaglutide has separately demonstrated reductions in major adverse cardiovascular events in large randomized trials, including a prespecified analysis of the SELECT trial examining outcomes by adiposity measurements.²

In the COVID-19 cohort, 30-day all-cause mortality occurred in 0.3% of patients with prior semaglutide use compared with 0.8% of metformin comparators (RR, 0.39; 95% CI, 0.24-0.64; P < .001).¹ Hospitalization occurred in 5.3% vs 7.4% (RR, 0.72; P < .001), and the composite outcome of death, hospitalization, intensive care admission, or mechanical ventilation occurred in 8.2% vs 10.6% (RR, 0.77; P < .001).¹ Differences in intensive care admission and mechanical ventilation alone did not reach statistical significance.¹

In the influenza cohort, mortality occurred in 0.2% of semaglutide-exposed patients compared with 0.7% of comparators (RR, 0.29; P = .03), hospitalization occurred in 6.5% vs 9.6% (RR, 0.68; P < .001), and the composite outcome occurred in 10.3% vs 14.6% (RR, 0.70; P < .001).¹ As in the COVID-19 cohort, differences in intensive care admission and mechanical ventilation alone were not statistically significant, which the study authors attributed in part to low absolute event counts, findings that build on prior evidence that metabolic disease and obesity independently raise the risk of severe COVID-19 outcomes.¹

Benefit Held Regardless of Vaccination Status

The association between semaglutide use and lower composite risk persisted regardless of prior vaccination status.¹ Among patients with COVID-19, the composite outcome was reduced in both unvaccinated patients (RR, 0.76; P < .001) and vaccinated patients (RR, 0.81; P = .04).¹ A similar pattern was observed in the influenza cohort among unvaccinated patients (RR, 0.69; P < .001), though the reduction among vaccinated patients did not reach statistical significance (RR, 0.74; P = .07).¹

Among organ-specific outcomes assessed, acute kidney injury was the only complication that remained significantly reduced in both cohorts after adjustment for multiple comparisons, with a relative risk of 0.73 in the COVID-19 cohort and 0.58 in the influenza cohort.¹ Reductions in acute coronary syndrome and pulmonary complications, including oxygen requirement and acute respiratory distress syndrome, were directionally consistent but did not reach statistical significance against the metformin comparator, consistent with a broader body of evidence tying metabolic health to infectious disease outcomes across multiple conditions.¹

Benefit Did Not Track With Weight Loss or Dose

In a secondary analysis restricted to semaglutide-treated patients, the composite outcome did not vary significantly across pre-infection weight loss strata of less than 5%, 5% to 15%, and 15% or more, nor across subcutaneous dosage strata ranging from 0.25 to 2.4 mg per week.¹ The study authors said this pattern suggests the observed reduction in infection severity may not be driven primarily by weight loss or by maximal dosing, potentially pointing toward broader immunomodulatory or metabolic mechanisms rather than a dose-dependent effect.¹

The researchers noted the study's observational design cannot establish causation, and that despite propensity-score matching across a broad set of covariates, unmeasured confounding remains possible.¹ The authors said the findings support prospective evaluation of low-dose semaglutide specifically to blunt the severity of respiratory viral infections, rather than immediate application to clinical practice based on observational data alone.¹

References

1. Matson R, Venkatakrishnan AJ, Murugadoss K, Soundararajan V. Semaglutide use linked to lower COVID-19 and influenza severity with better renal outcomes after pandemic or seasonal infection. Biol Methods Protoc. 2026;11(1):bpag042. doi:10.1093/biomethods/bpag042

2. Deanfield J, Lincoff AM, Kahn SE, et al. Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial. Lancet. 2025;406:2257-2268.