Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis

Abstract

Background: Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This K(ATP)-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection.

Methods: We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea.

Results: Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P = .04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio .47, 95% confidence interval .28-.74, P = .005). We identified differential expression of 63 immune-related genes (P = .001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group.

Conclusions: We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system.

Figure 1.

Summary of patient recruitment for cohort study.

Figure 2.

Kaplan-Meier survival curves of 1160 patients with melioidosis. The survival curves in panel A show that patients with diabetes have a survival advantage after the development of melioidosis, but the survival curves in panel B indicate that this effect was seen only in the patient group taking glyburide. The P values reported are for the log-rank test. Median duration of follow-up was 6.5 days and total follow-up was 11,845 patient days.

Figure 3.

Differential expression of inflammation-associated genes in diabetic patients with acute melioidosis with or without glyburide (Gb). Genes that are up-regulated are shown in red, down-regulated in green; genes in black are not differentially expressed. The gene symbols used are those assigned by the HUGO gene nomenclature committee.