High-Dose Flu Vaccine Reduces Hospitalizations in Older Adults with Diabetes, Danish Trial Shows
Key Insights
A secondary analysis of the DANFLU-2 trial involving over 332,000 older adults found that high-dose influenza (search) vaccines reduced hospitalizations for cardiorespiratory disease (search), cardiovascular disease (search), and influenza compared to standard-dose vaccines.
The protective benefits were consistent in adults with and without diabetes (search), though people with diabetes experienced greater absolute benefit due to their higher baseline risk for flu-related complications.
High-dose vaccination showed enhanced protection in individuals with diabetes (search) of longer duration (five years or more) and those with diabetes-related complications, suggesting potential for targeted prevention strategies.
A large-scale Danish clinical trial analysis has demonstrated that high-dose influenza (search) vaccines provide superior protection against severe respiratory and cardiovascular hospitalizations in adults aged 65 and older, with particularly notable benefits for those with diabetes (search). The findings, published in JAMA Internal Medicine, represent one of the largest individually randomized influenza vaccine trials conducted to date.
Trial Design and Participants
The secondary analysis of the DANFLU-2 randomized clinical trial included 332,438 older adults in Denmark vaccinated across three flu seasons from 2022-23 through 2024-25. Of the total participants, approximately 44,000 (13%) had diabetes (search), making this the largest trial to specifically include people with diabetes in influenza (search) vaccine research.
Participants were randomly assigned to receive either a high-dose inactivated influenza vaccine (HD-IIV), containing four times the antigen levels of standard vaccines, or a standard-dose inactivated influenza vaccine (search) (SD-IIV). Researchers used nationwide health registries to track respiratory and cardiovascular hospitalizations from 14 days after vaccination through May 31 of the following year.
Significant Reduction in Hospitalizations
The analysis revealed consistent protective benefits of high-dose vaccination across multiple endpoints. Receipt of HD-IIV was associated with notable reductions in hospitalizations compared to SD-IIV:
- Cardiorespiratory disease: 7.4% relative vaccine effectiveness (rVE) in diabetes patients, 5.3% rVE in non-diabetic patients
- Cardiovascular disease: 12.0% rVE in diabetes patients, 6.0% rVE in non-diabetic patients
- Influenza: 41.6% rVE in diabetes patients, 44.3% rVE in non-diabetic patients
The protective benefits of the high-dose vaccine were similar in people with and without diabetes (search), demonstrating consistent efficacy across diabetes status.
Enhanced Benefits for High-Risk Diabetes Patients
While HD-IIV offered protective benefits to all older adults, the research team from Copenhagen University Hospital noted it may confer "greater absolute benefit" to people with diabetes (search). This enhanced benefit stems from the higher baseline risk that diabetic patients face for serious flu-related complications, making each vaccination more likely to prevent serious illness in this population.
The analysis revealed particularly strong protection for specific diabetes (search) subgroups. HD-IIV offered greater protection to those who had diabetes for five years or longer, as well as those with diabetes-related complications, compared to those with less severe cases.
"Although exploratory and requiring confirmation in future research, these findings could imply that for certain end points, the protective benefits of HD-IIV compared with SD-IIV may be more prominent in individuals with more advanced diabetes (search)," the researchers wrote.
Clinical Implications and Mechanisms
The researchers hypothesize that individuals with greater diabetes (search) disease burden may have a suboptimal immune response to standard-dose vaccination, as well as increased susceptibility to flu-related complications. This could explain why the high-dose vaccine showed enhanced effectiveness in patients with longer diabetes duration and more complications.
The study found a higher risk of hospitalization due to cardiorespiratory and cardiovascular complications in participants with diabetes (search) compared to those without diabetes, highlighting the importance of optimizing preventive strategies for this high-risk population.
Study Limitations and Future Directions
The researchers emphasized that several diabetes (search)-specific estimates were imprecise and not statistically significant, and the subgroup analyses should be considered exploratory. The DANFLU-2 trial data were not specifically powered for subgroup analyses, and the study lacked access to follow-up laboratory data such as glycated hemoglobin levels.
Additionally, the trial could not determine treatment patterns, including the use of newer diabetes (search) medications such as glucagon-like peptide 1 receptor agonists (search) and sodium-glucose cotransporter-2 inhibitors (search), which may influence cardiovascular outcomes.
The findings "suggest that the effects of HD-IIV vs SD-IIV against severe respiratory and cardiovascular outcomes remain consistent regardless of diabetes (search) status" and "underscore the importance of influenza (search) vaccination and suggest potential benefit of HD-IIV compared with SD-IIV in individuals with diabetes," according to the research team.
These results support the current U.S. recommendation for high-dose vaccination in adults aged 65 years or older and provide new evidence for its particular value in diabetic patients within this age group.