Key Points: In veterans with type 2 diabetes and low kidney failure risk, sodium-glucose cotransporter 2 inhibitors (SGLT2is) were more kidney protective while glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were more cardioprotective. For cardiovascular-kidney-metabolic outcomes, GLP-1 RAs were more protective at moderate kidney failure risk and SGLT2is were more protective at high kidney failure risk. The kidney failure risk equation might be a clinically useful tool to guide therapy in type 2 diabetes. Background: Head-to-head comparisons of non-exendin glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) on kidney failure or cardiovascular-kidney-metabolic (CKM) composite end points are lacking. Whether kidney failure risk modifies the comparative effectiveness of GLP-1 RA versus SGLT2i is clinically relevant. Methods: We defined a national veterans cohort with type 2 diabetes who initiated an SGLT2i, non-exendin GLP-1 RA, or insulin glargine between January 1, 2018, and December 31, 2021. After applying inverse probability of treatment weighting to balance baseline characteristics, outcomes were compared across new-user groups through March 31, 2023. Outcomes included kidney failure (stage 5 CKD or long-term KRT), major adverse cardiovascular events (MACEs: heart failure, myocardial infarction, or stroke), CKM composite (kidney failure or MACE), all-cause death, and composites of outcomes with death. We tested for effect modification by the kidney failure risk equation (KFRE) score on comparative pairwise drug effectiveness. Results: Out of 160,428 veterans, 53%, 14%, and 34% were new users of SGLT2i, GLP-1 RA, and insulin glargine, respectively. Relative to GLP-1 RA new-users, SGLT2i new-users had similar mortality risk, a trend toward lower kidney failure risk (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.74 to 1.06), but higher risk of MACE (HR, 1.14; 95% CI, 1.09 to 1.20) and CKM composite (HR, 1.13; 95% CI, 1.08 to 1.19). The effect of SGLT2i versus GLP-1 RA differed significantly between moderate-risk (2%–6%) and high-risk (≥6%) KFRE subgroups for all outcomes except all-cause death. In those with moderate-risk KFRE, GLP-1 RA seemed more protective for kidney failure, MACE, and CKM composite, while SGLT2i appeared more protective in those with high-risk KFRE. Conclusions: Compared with GLP-1 RA, SGLT2i had comparable risks of mortality, perhaps a lower risk of kidney failure, but modestly higher risk of cardiovascular events in the entire cohort. However, GLP-1 RA were more beneficial in those with moderate kidney failure risk and SGLT2i more beneficial in those with high kidney failure risk.

Mycoplasma spp. are facultative pathogens that contribute to the pathogenesis of multiple bovine diseases, including the bovine respiratory disease complex, and have been shown to form biofilms. Biofilm formation is associated with increased antibiotic resistance in many organisms, but accurate determination of antimicrobial susceptibility in biofilms is challenging. In Mycoplasma spp., antimicrobial susceptibility is routinely determined using metabolic pH-dependent color change. However, biofilm formation can lead to reduced metabolism, making interpretation of metabolic readouts difficult. Therefore, we developed and optimized a new flow cytometry-based method for antimicrobial susceptibility testing in biofilm-forming Mycoplasma, termed the live/dead antimicrobial susceptibility test (LD-AST). The LD-AST measures the proportion of live bacteria upon exposure to antibiotics, works robustly with both planktonic and biofilm cultures, and enables the determination of the minimum bactericidal concentration (MBC) for a given antibiotic. We used two strains of Mycoplasma bovis (Donetta PG45 and Madison) and two clinical Mycoplasma bovoculi isolates (MVDL1 and MVDL2) to determine the impact of biofilm growth on antimicrobial susceptibility for gentamicin, enrofloxacin, or tetracycline. All Mycoplasma strains were susceptible to all antibiotics when cultured as planktonic cells, with MBCs in the expected range. However, three out of four strains (Donetta PG45, MVDL1, and MVDL2) were completely resistant to all three antibiotics when newly adhered biofilms were analyzed, whereas M. bovis Madison gave variable results. For mature biofilms that were cultured for 4–5 days before antibiotic exposure, results also were variable, with some strains showing an increased resistance with certain antibiotics and a decreased resistance with others. Overall, these results are consistent with earlier reports that biofilms can exhibit increased antimicrobial resistance.

In this pilot study, we identified rural veterans with chronic kidney disease and type 2 diabetes who have an indication for SGLT2i or GLP-1 RA but not yet on either of these agents. Nearly a third of providers changed their practice based on automatic e-consult; however, there were still 69% of cases where providers did not.