Dapagliflozin and Kidney Outcomes in Hospitalized Patients with COVID-19 Infection: An Analysis of the DARE-19 Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Patients who were hospitalized with coronavirus disease 2019 (COVID-19) infection are at high risk of AKI and KRT, especially in the presence of CKD. The Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial showed that in patients hospitalized with COVID-19, treatment with dapagliflozin versus placebo resulted in numerically fewer participants who experienced organ failure or death, although these differences were not statistically significant. We performed a secondary analysis of the DARE-19 trial to determine the efficacy and safety of dapagliflozin on kidney outcomes in the overall population and in prespecified subgroups of participants defined by baseline eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The DARE-19 trial randomized 1250 patients who were hospitalized (231 [18%] had eGFR <60 ml/min per 1.73 m2) with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. Dual primary outcomes (time to new or worsened organ dysfunction or death, and a hierarchical composite end point of recovery [change in clinical status by day 30]), and the key secondary kidney outcome (composite of AKI, KRT, or death), and safety were assessed in participants with baseline eGFR <60 and ≥60 ml/min per 1.73 m2. RESULTS: The effect of dapagliflozin versus placebo on the primary prevention outcome (hazard ratio, 0.80; 95% confidence interval, 0.58 to 1.10), primary recovery outcome (win ratio, 1.09; 95% confidence interval, 0.97 to 1.22), and the composite kidney outcome (hazard ratio, 0.74; 95% confidence interval, 0.50 to 1.07) were consistent across eGFR subgroups (P for interaction: 0.98, 0.67, and 0.44, respectively). The effects of dapagliflozin on AKI were also similar in participants with eGFR <60 ml/min per 1.73 m2 (hazard ratio, 0.71; 95% confidence interval, 0.29 to 1.77) and ≥60 ml/min per 1.73 m2 (hazard ratio, 0.69; 95% confidence interval, 0.37 to 1.29). Dapagliflozin was well tolerated in participants with eGFR <60 and ≥60 ml/min per 1.73 m2. CONCLUSIONS: The effects of dapagliflozin on primary and secondary outcomes in hospitalized participants with COVID-19 were consistent in those with eGFR below/above 60 ml/min per 1.73 m2. Dapagliflozin was well tolerated and did not increase the risk of AKI in participants with eGFR below or above 60 ml/min per 1.73 m2.

Hyperglycemia and dyslipidemia: Reduced HLA-DR expression in monocyte subpopulations from diabetes patients.

Immune dysfunction contributes to the higher risk of communicable and non-communicable diseases among diabetics. HLA-DR expression is a robust marker of immune competence in mononuclear cells, including antigen presentation to CD4 lymphocytes. Given the high prevalence of obesity among diabetics, we evaluated the independent association between hyperglycemia and dyslipidemias with respect to HLA-DR expression in blood monocytes from type 2 diabetes patients. The monocytes from individuals with (n = 16) or without diabetes (n = 25) were phenotyped by flow cytometry to assess the differential expression of HLA-DR on their three subpopulations (classical, intermediate and non-classical monocytes). Diabetes was independently associated with lower HLA-DR expression across all monocyte subpopulations (p < 0.05). Blood triglycerides were associated with further HLA-DR depression (interaction p < 0.002). Cholesterols counterbalanced the reductive effect, with CD36, a receptor for oxidized cholesterol, correlating with HLA-DR (rho = 0.373; p = 0.016). Future studies are warranted to elucidate the complex interactions between hyperglycemia and dyslipidemias on antigen presentation in diabetic monocytes.

Phagocytosis via complement or Fc-gamma receptors is compromised in monocytes from type 2 diabetes patients with chronic hyperglycemia.

Type 2 diabetes patients (DM2) have a higher risk of tuberculosis (TB) that may be attributed to functional defects in their mononuclear phagocytes given the critical role of these cells in Mycobacterium tuberculosis containment. Our previous findings suggest that monocytes from DM2 have reduced association with serum-opsonized M. tuberculosis. To determine if this alteration is due to defects in phagocytosis via complement or Fc-gamma receptors (FcγRs), in this study we evaluated the uptake of sheep red blood cells coated with IgG or complement, respectively, by monocytes from individuals with and without DM2. We found that chronic hyperglycemia was significantly associated with reduced phagocytosis via either receptor by univariable and multivariable analyses. This defect was independent of host serum opsonins and flow cytometry data indicated this was not attributed to reduced expression of these phagocytic receptors on DM2 monocytes. The positive correlation between both pathways (R = 0.64; p = 0.003) indicate that monocytes from individuals with chronic hyperglycemia have a defect in the two predominant phagocytic pathways of these cells. Given that phagocytosis is linked to activation of effector mechanisms for bacterial killing, it is likely that this defect is one factor contributing to the higher susceptibility of DM2 patients to pathogens like M. tuberculosis.

Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control.

The re-emerging importance of type 2 diabetes mellitus (DM) to tuberculosis (TB) control is of growing concern, but the basis for this relationship is poorly understood. Given the importance of mononuclear phagocytes for TB control and the reported alterations in monocytes of DM patients, we evaluated whether the initial interaction between both was affected in diabetics. Mycobacterium tuberculosis-naïve individuals with and without DM were group matched by age and gender and the efficiency of M. tuberculosis association (attachment and ingestion) with their monocytes was assessed in the presence of autologous serum. The association of M. tuberculosis with monocytes was significantly lower in diabetics (19.2 ± 6.1) than non-diabetics (27.5 ± 7.9; p = 0.02). Multivariate analysis controlling for host socio demographics, DM characteristics and serum lipids indicated that male gender (p = 0.04) and poorly-controlled DM (high HbA1c and hyperglycemia; p = 0.01) were significantly associated with the lower interaction of M. tuberculosis with monocytes. Serum heat-inactivation reduced the association of M. tuberculosis to similar levels in both study groups (p = 0.69) suggesting alterations in the complement pathway of DM patients. These findings suggest an altered route of entry of the pathogen in DM patients that may influence the downstream activation of signaling pathways in the monocyte and the survival of mycobacteria.