Effects of Empagliflozin on Fluid Overload, Weight, and Blood Pressure in CKD.

SIGNIFICANCE STATEMENT: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment. Empagliflozin induced a prompt and sustained reduction in "Fluid Overload," irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk. BACKGROUND: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03594110 ; EuDRACT: 2017-002971-24 ( https://eudract.ema.europa.eu/ ).

Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.

BACKGROUND: In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death. METHODS: We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected. RESULTS: Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01). CONCLUSIONS: The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.

Spectroscopic diagnosis of myocardial infarction and heart failure by Fourier transform infrared spectroscopy in serum samples.

Cardiovascular disease is the leading cause of death in Western civilization. In this pilot study we evaluated a new method for the diagnosis of myocardial infarction and heart failure by determining the typical fingerprint in the infrared (IR) spectrum of 1 microL of a dried patient serum sample by Fourier transform IR spectroscopy. For classification, cluster analysis and artificial neural networks (ANN) were applied. In this study 567 subjects were enrolled, comprising 225 controls (Co) and 342 patients with myocardial infarction (MI) (n = 157) and heart failure (HF) (n = 185). By applying artificial neural network algorithms, the following sensitivities and specificities of the same spectra were determined: MI versus Co (98%, 97%), HF versus Co (98%, 100%), MI versus HF (100%, 100%), and MI plus HF versus Co (100%, 100%). Based on our data, mid-IR spectroscopy appears to be a promising new method to diagnose heart diseases from serum samples. Artificial neural network algorithms proved to be superior to cluster analysis for correct prediction.

Biological relevance of anti-recombinant hirudin antibodies--results from in vitro and in vivo studies.

This article provides an overview of the clinically relevant characteristics of antibodies directed toward recombinant (r) hirudin, with emphasis on the different ways in which these antibodies may influence pharmacokinetics and pharmacodynamics of r-hirudin. A high incidence of anti-hirudin antibody (AHAb) formation, mainly of the immunoglobulin G (IgG) subclass, was reported in up to 74% of patients treated with r-hirudin for more than 5 days. Like other drug-induced antibodies, AHAb may be responsible for accumulation or neutralization of the drug. Current clinical data support this assumption with reports on reduced metabolism, enhanced activity, and accumulation and neutralization of r-hirudin in the presence of AHAb. By examining AHAb developed in patients, we were able to demonstrate that AHAbs are capable of neutralizing r-hirudin in vitro. In addition, the anticoagulant activity of r-hirudin administered to Sprague-Dawley rats was almost completely abolished when a monoclonal mouse AHAb with known r-hirudin neutralizing capacity in vitro was injected intravenously. Because r-hirudin is mainly eliminated via the kidneys, formation of r-hirudin-AHAb complexes may, due to their size, result in accumulation of r-hirudin. We investigated filtration of r-hirudin incubated with monoclonal mouse AHAb by using high-flux hemodialyzers in a suitable in vitro model. Whereas sieving coefficients (SC) were high in the absence of AHAb, they were minimal (SC < 0.05) in the presence of AHAb. These findings may also be important when AHAb-positive patients treated with r-hirudin undergo hemofiltration procedures, which have recently been described as a rescue measure in case of r-hirudin overdosage. In vivo, the influence of a non-neutralizing monoclonal mouse AHAb on r-hirudin pharmacokinetics was examined in rats. Pharmacokinetic data compared with those of a control group without AHAb administration revealed that r-hirudin elimination half-life was significantly prolonged (59 +/- 25 minutes versus 142 +/- 25 minutes). This was accompanied by a decrease of total plasma clearance of r-hirudin. The volume of distribution of r-hirudin was significantly decreased (275 +/- 112 mL/kg versus 35 +/- 3 mL/kg), indicating that r-hirudin bound by AHAb is mainly distributed to the intravascular compartment. Taken together, both the half-life prolongation and the decrease of the volume of distribution contribute to r-hirudin accumulation and may explain respective findings in patients. In summary, two different effects of AHAbs seem to be clinically relevant: decreasing anticoagulant activity of r-hirudin by neutralization and accumulation of r-hirudin by reducing renal clearance. Formation of AHAbs has not yet been correlated with enhanced major bleeding complications. However, close monitoring of coagulation parameters is recommended in AHAb-positive patients during r-hirudin treatment.