Prior Use of GLP-1 Receptor Agonists versus SGLT2 Inhibitors and Clinical Outcomes After Sepsis in Patients with Type 2 Diabetes: A Propensity Score-Matched Cohort Study.

Background: Whether pre-existing glucose-lowering therapy influences outcomes after sepsis remains uncertain. We compared clinical outcomes among patients with type 2 diabetes (T2D) who developed sepsis according to prior GLP-1 receptor agonists (GLP-1RAs) or SGLT2 inhibitors (SGLT2is) use. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network. Adults with T2D who developed sepsis had received a GLP-1RA or an SGLT2i within 3 months before sepsis were identified. After 1:1 propensity score matching, 11,969 patients were included in each group. The primary outcome was 90-day all-cause mortality. Secondary outcomes included major adverse cardiovascular event (MACE), major adverse kidney event (MAKE), intensive care unit (ICU) admission, major adverse cardiac and cerebrovascular event (MACCE), septic shock, and acute respiratory failure. Results: Compared with prior SGLT2i use, prior GLP-1RA use was associated with lower 90-day all-cause mortality (incidence rate, 48.6 vs 60.6 per 100 person-years; HR, 0.81; 95% CI, 0.75-0.88; E-value: 1.6) and lower risks of MACE (HR, 0.77; 0.65-0.91; E-value, 1.7), myocardial infarction (HR, 0.82; 0.67-0.99; E-value, 1.7), ICU admission (HR, 0.89; 0.84-0.94; E-value, 1.4), and MACCE (HR, 0.86; 0.74-0.99; E-value, 1.5). No significant difference was observed for septic shock (HR, 0.87; 95% CI, 0.74-1.02), acute respiratory failure (HR, 0.94; 95% CI, 0.83-1.06), or MAKE (HR, 1.08; 95% CI, 0.92-1.27). The mortality benefit remained consistent through 365 days and across all prespecified subgroups. After Holm correction for multiple comparisons across the seven secondary outcomes, only the associations with MACE (adjusted P=0.012) and ICU admission (adjusted P<0.007) remained statistically significant, while those with MACCE, myocardial infarction, MAKE, septic shock, and acute respiratory failure did not. Conclusion: Among patients with T2D who developed sepsis, prior GLP-1RA use was associated with lower mortality and select cardiovascular/renal risks than prior SGLT2i use, though roughly half of secondary outcomes showed no significant difference. Exposure was defined at the drug-class rather than individual-agent level, and modest E-values alongside baseline imbalances before matching suggest residual confounding cannot be excluded. These hypothesis-generating findings warrant confirmation in prospective studies.