Metformin Is Associated with Reduced Risk of Sepsis: Analysis of a U.S. Cohort from 2009-2019

OBJECTIVES:

The global rates of sepsis and sepsis-related mortality have not significantly declined. Metformin, a first-line medication for type two diabetes mellitus (T2DM), has been found to have immunomodulatory effects in aging, cancer, and in high inflammatory states (e.g. severe infections/sepsis), highlighting its potential role in preventative-medicine; however, real-world studies are lacking. This study evaluated whether metformin-use is associated with lower risks for all-cause sepsis.

METHODS:

This was a retrospective U.S. cohort analysis of third-party medical and pharmacy claims databases from 2009 to 2019. Adults 18 years of age and older who received a routine pneumococcal vaccine (index date) and were continuously enrolled for at least one year before and after were included. Diagnosis of all-cause sepsis during hospitalization was determined using ICD-9/10-CM codes within one year from the index date. Metformin-use was defined as having at least a 90-day supply prior to index date. The primary outcome of all-cause sepsis was analyzed using multivariable logistic-regression models stratified by T2DM status.

RESULTS:

Overall, 600,132 adults met inclusion; the median age was 65 years, 45.1% were males, and 25.9% had T2DM. Among the 44,346 metformin-users (median dose=1,000 mg/day), 84.4% (n=37,420) had T2DM and 15.6% did not have T2DM (n=6,929); there were no differences in baseline demographics. The overall rate of sepsis within 1 year was 0.43%. Overall, metformin-use was associated with lower risks of sepsis (aOR 0.847, 95% CI 0.721-0.995) after adjusting for age, sex, year, and co-morbidities. This protective effect of metformin-use was observed when stratified among metformin-users without T2DM (aOR 0.549, 95% CI 0.327-0.920), but not among those with T2DM (aOR 0.920, 95% CI 0.768-1.103).

CONCLUSIONS:

Metformin-use was associated with reduced risk of sepsis among persons without T2DM, underscoring the need for future investigations to identify populations who might benefit from metformin.