High-Dose vs Standard-Dose Influenza Vaccine in Older Adults With Diabetes: A Secondary Analysis of the DANFLU-2 Randomized Clinical Trial
In adults 65 years or older, a high-dose influenza vaccine modestly reduced several hospitalization outcomes compared with a standard-dose vaccine, with similar benefit in people with and without diabetes.
*Pragmatic open-label randomized clinical trial (secondary analysis); Level 1b.
*Pragmatic open-label randomized clinical trial (secondary analysis); Level 1b.
Citation
Nielsen AB, Johansen ND, Modin D, et al. High-dose vs standard-dose influenza vaccine in older adults with diabetes: a secondary analysis of the DANFLU-2 randomized clinical trial. JAMA Internal Medicine. 2026;186(3):311-320. doi:10.1001/jamainternmed.2025.7286
Background
Older adults, especially those with diabetes, have higher risks of severe illness from influenza. High-dose influenza vaccines prevent influenza infection better than standard-dose vaccines, but evidence for severe heart and lung outcomes in diabetes has been limited.
Patients
Adults 65 years or older in Denmark (2022/2023 to 2024/2025 influenza seasons); no formal exclusion criteria. Total: 332,438 participants; 43,881 had diabetes.
Intervention
High-dose inactivated influenza vaccine (single seasonal injection).
Control
Standard-dose inactivated influenza vaccine.
Outcome
Hospitalizations for combined heart/lung disease, heart disease, influenza, lab-confirmed influenza, and heart failure; comparison by diabetes status and diabetes subgroups.
Follow-up Period
From 14 days after vaccination to May 31 each season.
Results
| Outcome | High-dose vs standard-dose (relative reduction) | NNT |
|---|---|---|
| Hospitalization for any heart/lung disease | 5.7% (1.4% to 9.9%) | 1000 |
| Hospitalization for any heart disease | 7.2% (1.5% to 12.5%) | 1000 |
| Hospitalization for influenza | 43.6% (27.6% to 56.2%) | 2132 |
| Hospitalization for lab-confirmed influenza | 35.9% (22.3% to 47.2%) | 1678 |
| Hospitalization for heart failure | 19.5% (3.3% to 33.1%) | 3205 |
Effects were generally similar in participants with and without diabetes. In exploratory subgroup analyses, people with diabetes for more than 5 years appeared to benefit more for some outcomes.
Analysis was intention-to-treat.
Limitations
Secondary and subgroup analyses were not the main trial focus and involved multiple comparisons without adjustment, so some findings may be due to chance. The trial was open-label and relied on registry records. Although relative reductions were significant for several outcomes, the absolute benefits were small (high NNTs), which may limit day-to-day clinical impact.
Funding
Sanofi; additional support from Danish cardiovascular research foundations.
Clinical Application
For adults 65+ (including diabetes), consider high-dose influenza vaccine when available; absolute benefit is modest, but may be larger in longer-standing diabetes.
Discussion
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In this prespecified secondary analysis of a pragmatic open-label randomized trial, HD-IIV vs SD-IIV reduced influenza hospitalization similarly in participants with diabetes (rVE 41.6%, 95% CI 5.0%-64.7%). Given the neutral primary trial endpoint and exploratory subgroups, should this change vaccine choice for older adults with diabetes? In this randomized trial analysis, the relative vaccine effectiveness of HD-IIV vs SD-IIV was broadly similar in adults with and without diabetes, but the number needed to vaccinate was lower in those with diabetes for several outcomes. What best explains this?