Background <p>This study aimed to investigate the impact of new-onset herpes zoster (HZ) on the risk of cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM) and to evaluate whether subsequent initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors modified this risk.</p> Methods <p>Patients with T2DM were identified from a territory-wide cohort from 2016 to 2021. The primary outcomes were primary renal composite outcomes (defined as a composite of end-stage renal failure, a 50% decline in estimated glomerular filtration rate [eGFR], or all-cause mortality) and primary cardiovascular composite outcomes (defined as a composite of heart failure hospitalization, myocardial infarction, stroke or all-cause mortality).</p> Results <p>New-onset HZ occurred in 3,306/171,474 patients (incidence rate 5.70/1,000 person-years) and was independently associated with higher risks of the primary renal composite outcomes (adjusted HR 1.42, 95% CI 1.30–1.55) and primary cardiovascular composite outcomes (adjusted HR 1.59, 95% CI 1.42–1.77) in patients with T2DM. This association was more pronounced within the first three months following infection and attenuated thereafter. Among patients who developed HZ, the initiation of SGLT2 inhibitors was associated with a lower risk of adverse renal (HR 0.57, 95% CI 0.42–0.78) and cardiovascular (HR 0.54, 95% CI 0.32–0.91) outcomes.</p> Conclusions <p>New-onset HZ was associated with increased cardiorenal risk among patients with T2DM, and subsequent SGLT2 inhibitors initiation was associated with a reduced risk of these adverse events. These findings underscore the significance of HZ prevention and the potential benefits of early initiation of SGLT2 inhibitors post-HZ to mitigate cardiorenal adverse events in patients with T2DM.</p> Clinical trial number <p>Not applicable.</p>