Abstract
BACKGROUND: Diabetes mellitus and sepsis are major contributors to mortality in the U.S., with increasing evidence of their clinical overlap. This study examines nationwide trends in diabetes and sepsis-related mortality from 1999 to 2024, stratified by sex, race/ethnicity, and geographic factors. METHODS: Mortality data for individuals aged ≥ 25 years from 1999 to 2024 was extracted from the CDC-WONDER database. Age-adjusted mortality rates (AAMRs) per 100,000 population were calculated. Trends over time were analyzed using Joinpoint regression to estimate annual percentage changes (APCs). We performed a time-series analysis using autoregressive integrated moving average (ARIMA) models to forecast AAMRs through 2030. RESULTS: From 1999 to 2024, 509,255 deaths were attributed to diabetes and sepsis. The overall AAMR was 8.88 in 1999, declined to 7.85 in 2018 (APC: -1.20; 95% CI: -1.90 to - 0.65), increased sharply to 12.08 in 2021 (APC: 17.32; 95% CI: 9.07 to 21.07), and then declined to 9.37 in 2024 (APC: -8.87; 95% CI: -14.91 to - 4.98). The forecasting analysis predicted an AAMR of 11.2 (95% CI: 6.9 to 15.5) in 2030. Males consistently had higher AAMRs than females (11.23 vs. 7.93 in 2024). The highest mortality burden was observed among NH Black individuals (15.66), followed by Hispanic or Latino (12.88), NH Other (9.10), and NH White (8.05) populations. Regionally, the South (10.95) experienced the highest mortality, followed by the West (10.4), Midwest (7.9), and Northeast (6.55). Rural areas showed consistently greater mortality than urban areas (8.81 vs. 8.18). CONCLUSION: Diabetes and sepsis-related mortality in the U.S. showed a declining trend until 2018, followed by a sharp rise during the pandemic and a subsequent decline. These findings highlight the need for targeted public health strategies to address persistent disparities and improve outcomes for vulnerable populations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-026-01874-y.