title: Effects of empagliflozin on fluid overload, weight and blood pressure in chronic kidney disease
Creators: name: Mayne, Kaitlin Jane
Publisher: name: University of Glasgow
Year: 2025

description: Background:
Chronic kidney disease (CKD) is common worldwide and associated with considerable morbidity and mortality, largely due to cardiovascular disease. As CKD progresses, fluid overload is a common manifestation which has both clinical and prognostic implications. Bioimpedance spectroscopy is commonly used in the dialysis setting to assess fluid status but less so in earlier stages of CKD.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to slow the progression of kidney disease and additionally have cardiovascular benefits. The underlying mechanisms of SGLT2 inhibitors remain incompletely understood but include diuretic effects and so they may reduce fluid overload. Trial reports demonstrate consistent treatment effects across a range of patient subgroups however these don’t address the real-life scenario in which the highest risk patients (such as those with frailty) exhibit several characteristics in combination. Clinicians may hesitate to prescribe SGLT2 inhibitors in patients with frailty (which is common in CKD) due to perceived altered risk-benefit profile.

The hypothesis of this work is that the beneficial effects of empagliflozin (an SGLT2 inhibitor) on kidney and cardiovascular outcomes in CKD may be in part explained by fluid reduction which can be assessed using bioimpedance spectroscopy. This work will explore potential contributory mechanisms (through effects on fluid overload and blood pressure) and whether there is heterogeneity of treatment effect (focusing on frailty).

Methods:
A systematic review was conducted to inform the analysis strategy for analyses of the effects of empagliflozin on fluid overload. The full methods of the EMPA-KIDNEY trial have been reported elsewhere. In brief, 6609 patients with CKD at risk of progression with an estimated glomerular filtration rate (eGFR) ≥20 and &lt;90 mL/min/1.73m2 were randomised to either empagliflozin or matching placebo. The primary outcome was the first occurrence of kidney disease progression or death from cardiovascular causes. An EMPA-KIDNEY bioimpedance substudy obtained bioimpedance measurements in addition to routine trial procedures at the randomisation, 2- and 18-month follow-up visits in 660 participants. Weight and blood pressure were measured at all visits. “Risk of hospitalisation during follow-up” at baseline was used as the primary frailty indicator with supplementary analyses by multimorbidity, polypharmacy and health-related quality of life at baseline.

Effects of empagliflozin on fluid status, blood pressure and weight were assessed using a mixed model repeated measures (MMRM) approach; and effects on binary endpoints were assessed using Cox regression models; with adjustment for age, sex, prior diabetes, eGFR, and urinary albumin-to-creatinine ratio (uACR) in the categories used in the minimised randomisation algorithm. Pre-specified subgroups were categories of sex, diabetes, eGFR and N-terminal pro B-type natriuretic peptide (NT-proBNP) and subgroup-specific treatment effects were estimated by fitting interaction terms in the MMRM or Cox models and calculating heterogeneity or trend statistics. Frailty (predicted risk of hospitalisation) was determined by logistic regression models with recorded hospitalisation (first event) as the response variable. All variables which were significantly associated (P&lt;0.01) with hospitalisation in univariable models proceeded to inclusion in multivariable model building using forward stepwise selection and likelihood ratio tests with significance threshold P&lt;0.01. Frailty subgroups were defined according to predicted risk of hospitalisation and relative and estimated absolute effects on the trial’s primary outcome and all-cause hospitalisation were assessed.

Results:
In 620 substudy participants included in the primary assessment, compared to placebo, the study-average absolute difference in absolute “Fluid Overload” was -0.24 L (95% CI -0.38, -0.11). Effects were similar at 2- and 18-months (-0.23 [-0.37, -0.08] and -0.26 [-0.46, -0.06] L, respectively; P value for interaction with time = 0.11) and across the pre-specified subgroups. There were no significant between-group differences in bioimpedance-derived fat or lean tissue parameters. In the bioimpedance substudy cohort, the study-average between-group difference in total body weight in kg was -0.7 kg (95% CI -1.3, -0.1), consistent with the -0.9 kg (95% CI -1.2, -0.6) difference observed in the full trial cohort. In the full trial, the effects on weight persisted over time (P for interaction = 0.47) with consistent effects across subgroups. The study-average between-group differences in systolic and diastolic blood pressure in the full trial cohort were -2.6 mmHg (95% CI -3.3, -1.9) and -0.5 mmHg (95% CI -0.9, -0.1), respectively with similar results in the substudy cohort. There was no evidence of heterogeneity of the blood pressure lowering effect of empagliflozin when subdivided by sex, baseline eGFR or NT-proBNP but there was some evidence to suggest greater systolic blood pressure lowering in patients with diabetes (-4.1 [0.3] versus -1.9 [0.3] mmHg; heterogeneity P value = 0.001).

Overall, compared to placebo, empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death by 28% (HR 0.72, 95% CI 0.64-0.82), with no significant difference in relative effects by baseline frailty (P for heterogeneity all &gt;0.05). In absolute terms, there was evidence of larger estimated benefits on the primary outcome in participants in the highest category of frailty (based on risk of hospitalisation) compared to those with lesser degrees of frailty: per 1000 participants treated, empagliflozin was estimated to result in 38 fewer primary outcomes among those in the highest frailty category compared to 14 primary outcomes avoided annually in the lowest third of frailty. Safety outcomes such as dehydration and bone fractures were more common in participants with indicators of increased frailty, but there was no significant effect of study treatment on any of these outcomes overall or among those who were most frail.

Conclusion:
The findings from this thesis demonstrate that the benefits of SGLT2 inhibitor treatment extend beyond the main effects on slowing kidney disease progression and provide some mechanistic insights into how these benefits are mediated. Empagliflozin resulted in sustained reductions in “Fluid Overload”, weight and blood pressure in patients with CKD with and without diabetes with no demonstrable effect on fat mass. This effect was evident even in patients with low levels of kidney function. In the studied population, the absolute benefits of empagliflozin on the primary outcome (kidney disease progression or cardiovascular death) were greater in patients with the highest levels of frailty and outweighed the absolute risks of adverse events.