Importance Influenza infection poses a substantial risk of severe complications, particularly in older adults and high-risk populations, such as individuals with diabetes. The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior efficacy against influenza infection compared with the standard-dose inactivated influenza vaccine (SD-IIV) among adults 65 years or older. However, there is limited evidence on its effectiveness in preventing severe respiratory and cardiovascular outcomes in individuals with diabetes. Objective To investigate the relative vaccine effectiveness (rVE) of HD-IIV vs SD-IIV against severe respiratory and cardiovascular outcomes according to diabetes status and across diabetes subgroups. Design, Setting, and Participants This was a prespecified secondary analysis of DANFLU-2, a pragmatic, open-label, individually randomized clinical trial conducted in Denmark during the 2022/2023 to 2024/2025 influenza seasons. Adults 65 years or older were eligible for inclusion regardless of comorbidities. Data were obtained from nationwide health registries and analyzed from June to October 2025. Interventions Participants were randomly allocated 1:1 to receive HD-IIV or SD-IIV. Main Outcomes and Measures Outcomes included respiratory and cardiovascular hospitalizations. The potential effect modification by diabetes status and across diabetes subgroups was tested. Results Among 332 438 participants (mean SD age, 73.7 5.8 years; 161 538 female individuals 48.6%), 43 881 (13.2%) had diabetes. Overall, HD-IIV compared with SD-IIV was associated with reduced cardiorespiratory hospitalization, cardiovascular hospitalization, and influenza hospitalization. Effect estimates were similar for participants with and without diabetes for cardiorespiratory hospitalization (diabetes: rVE, 7.4%; 95% CI, −2.5% to 16.3%; no diabetes: rVE, 5.3%; 95% CI, 0.4%-10.0%; interaction P = .69), cardiovascular hospitalization (diabetes: rVE, 12.0%; 95% CI, −0.9% to 23.3%; no diabetes: rVE, 6.0%; 95% CI, −0.4% to 12.0%; interaction P = .38), and influenza hospitalization (diabetes: rVE, 41.6%; 95% CI, 5.0%-64.7%, vs no diabetes: rVE, 44.3%; 95% CI, 25.3%-58.7%; interaction P = .87). Duration of diabetes appeared to modify the effect of HD-IIV vs SD-IIV for cardiorespiratory hospitalization, with suggested benefit of HD-IIV in participants with diabetes duration longer than 5 years (rVE, 20.4%; 95% CI, 5.3%-33.1%), but not in those with shorter duration (rVE, −0.4%; 95% CI, −13.8% to 11.5%; interaction P = .03). Conclusions and Relevance The trial results suggest that, among adults 65 years or older, HD-IIV provided consistent benefit for cardiorespiratory, cardiovascular, and influenza hospitalizations compared with SD-IIV, regardless of diabetes status. Trial Registration ClinicalTrials.gov Identifier: NCT05517174
Nielsen et al. (Mon,) studied this question.