TY - JOUR
T1 - High-Dose vs Standard-Dose Influenza Vaccine in Older Adults With Diabetes
T2 - A Secondary Analysis of the DANFLU-2 Randomized Clinical Trial
AU - Nielsen, Anne Bjerg
AU - Johansen, Niklas Dyrby
AU - Modin, Daniel
AU - Loiacono, Matthew M
AU - Harris, Rebecca C
AU - Dufournet, Marine
AU - Larsen, Carsten Schade
AU - Larsen, Lykke
AU - Wiese, Lothar
AU - Dalager-Pedersen, Michael
AU - Claggett, Brian L
AU - Janstrup, Kira Hyldekær
AU - Bartholdy, Katja Vu
AU - Bernholm, Katrine Feldballe
AU - Borchsenius, Julie Inge-Marie Helene
AU - Davidovski, Filip Søskov
AU - Davodian, Lise Witten
AU - Dons, Maria
AU - Duus, Lisa Steen
AU - Espersen, Caroline
AU - Fussing, Frederik Holme
AU - Jensen, Anne Marie Reimer
AU - Landler, Nino Emanuel
AU - Langhoff, Adam Cadovius Femerling
AU - Lassen, Mats Christian Højbjerg
AU - Ottosen, Camilla Ikast
AU - Sengeløv, Morten
AU - Skaarup, Kristoffer Grundtvig
AU - Pareek, Manan
AU - Müller-Wieland, Dirk
AU - Solomon, Scott D
AU - Landray, Martin J
AU - Gislason, Gunnar H
AU - Køber, Lars
AU - Sivapalan, Pradeesh
AU - Martel, Cyril Jean-Marie
AU - Jensen, Jens Ulrik Stæhr
AU - Biering-Sørensen, Tor
PY - 2026/1/12
Y1 - 2026/1/12
N2 - 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.
AB - 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.
U2 - 10.1001/jamainternmed.2025.7286
DO - 10.1001/jamainternmed.2025.7286
M3 - Journal article
C2 - 41525066
SN - 2168-6106
JO - JAMA Internal Medicine
JF - JAMA Internal Medicine
ER -