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Aims Hyperkalaemia frequently leads to interruption and discontinuation of neurohormonal antagonists, which may worsen heart failure prognosis. Some studies suggested that sodium-glucose cotransporter 2 inhibitors reduce hyperkalaemia, an effect that may have important clinical implications. This analysis evaluates the effect of empagliflozin on the occurrence of hyper- and hypokalaemia in HF. Methods and results EMPEROR-Pooled (i.e. EMPEROR-Reduced and EMPEROR-Preserved combined) included 9583 patients with available serum potassium levels at baseline (98.6% of the total EMPEROR-Pooled population, n = 9718). Hyperkalaemia was identified by investigators’ reports of adverse events, and by a laboratory serum potassium value above 5.5 mmol/L and 6.0 mmol/L. The main outcome was a composite of investigator-reported hyperkalaemia or initiation of potassium binders. Patients with high potassium at baseline were more frequently diagnosed with diabetes and ischaemic HF aetiology and had lower left ventricular ejection fraction and estimated glomerular filtration rate but were more frequently treated with sacubitril/valsartan or mineralocorticoid receptor antagonists. Empagliflozin (compared with placebo) reduced the composite of investigator-reported hyperkalaemia or initiation of potassium binders [6.5% vs. 7.7%, hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71–0.95, P = 0.01]. Empagliflozin reduced hyperkalaemia rates regardless of the definition used (serum potassium >5.5 mmol/l: 8.6% vs. 9.9%, HR 0.85, 95% CI 0.74–0.97, P = 0.017; serum potassium >6.0 mmol/l: 1.9% vs. 2.9%, HR 0.62, 95% CI 0.48–0.81, P Conclusions Empagliflozin reduced the incidence of hyperkalaemia without significant increase in hypokalaemia.

OBJECTIVE To assess the safety of empagliflozin in patients with type 2 diabetes and moderate to severe chronic kidney disease (CKD) (category G3–4) enrolled in clinical trials. RESEARCH DESIGN AND METHODS This analysis pooled data from 19 randomized, placebo-controlled, phase 1–4 clinical trials and 1 randomized, placebo-controlled extension study in which patients received empagliflozin 10 mg or 25 mg daily. Time to first occurrence of adverse events (AEs) was evaluated using Kaplan-Meier analysis and multivariable Cox regression models. RESULTS Among a total of 15,081 patients who received at least one study drug dose, 1,522, 722, and 123 were classified as having G3A, G3B, and G4 CKD, respectively, at baseline. Demographic and clinical characteristics were similar between treatment groups across CKD categories. Rates of serious AEs, AEs leading to discontinuation, and events of special interest (including lower limb amputations and acute renal failure [ARF]) were also similar between empagliflozin and placebo across CKD subgroups. In adjusted Cox regression analyses, risks for volume depletion and ARF were similar for empagliflozin and placebo in the combined group with CKD categories G3B and G4 and the G3A group. Notably lower risks were observed in both groups for hyperkalemia (hazard ratio 0.59 [95% CI 0.37–0.96, P = 0.0323] and 0.48 [0.26–0.91, P = 0.0243], respectively) and edema (0.47 [0.33–0.68, P < 0.0001] and 0.44 [0.28–0.68, P = 0.0002], respectively). CONCLUSIONS Use of empagliflozin in patients with type 2 diabetes and advanced CKD raised no new safety concerns and may have beneficial effects on the development of hyperkalemia and edema.

Treatment with sodium-glucose co-transporter-2 inhibitors induces an initial 3-5 ml/min/1.73 m(2) decline in estimated glomerular filtration rate (eGFR). Although considered to be of hemodynamic origin and largely reversible, this 'eGFR dip' may cause concern in clinical practice, which highlights the need to better understand its incidence and clinical implications. In this post hoc analysis of the EMPA-REG OUTCOME trial, 6,668 participants randomized to empagliflozin 10 mg, 25 mg or placebo with eGFR available at baseline and week four were categorized by initial eGFR change into three groups; over 10% decline ('eGFR dipper'), over 0 and up to 10% decline ('eGFR intermediate'), no eGFR decline ('eGFR non-dipper'). Baseline characteristics of 'eGFR intermediate' and 'eGFR non-dipper' were generally comparable. An initial 'eGFR dip' was observed in 28.3% of empagliflozin versus 13.4% of placebo-treated participants; odds ratio 2.7 [95% Confidence Interval 2.3-3.0]. In multivariate logistic regression, diuretic use and higher KDIGO risk category at baseline were independently predictive of an 'eGFR dip' in empagliflozin versus placebo. Safety and beneficial treatment effects with empagliflozin on cardiovascular and kidney outcomes were consistent across subgroups based on these predictive factors. The initial 'eGFR dip' did not have a major impact on the treatment effect of empagliflozin on subsequent cardiovascular death, hospitalization for heart failure, and incident or worsening kidney disease. Thus, patients with type 2 diabetes with more advanced kidney disease and/or on diuretic therapy were more likely to experience an 'eGFR dip' of over 10% with empagliflozin, but reduction in cardiovascular and kidney outcomes was not relevantly modified by such 'eGFR dip.'

Aims The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). Methods and results HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were −4.0 m (−16.0, 6.0; P = 0.42) and 4.0 m (−5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported. Conclusion The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

In EMPA-REG OUTCOME, empagliflozin (EMPA) reduced the risk of CV death by 38% in T2D patients (pts) with CV disease. EMPA induces an initial, reversible dip in estimated glomerular filtration rate (eGFR). We investigated whether this transient initial renal hemodynamic effect was influenced by baseline characteristics or had an impact on the EMPA-induced risk reduction in CV death. In a post-hoc analysis, among the 6,668 pts randomized to EMPA 10 mg, 25 mg or placebo [PBO] with eGFR available, 28.3% of EMPA pts vs. 13.4% PBO experienced an initial eGFR decline >10% from baseline to Week 4 (odds ratio [OR; 95% CI]: 2.7 [2.3-3.0]). Multivariate logistic regression was used to identify baseline characteristics predictive of eGFR dip >10%. The impact of an eGFR dip >10% on the risk reduction in CV death was assessed using Cox regression. Diuretic use and higher KDIGO (Kidney Disease: Improving Global Outcomes) risk category at baseline were predictive of an eGFR dip >10% with EMPA vs. PBO. Serious adverse events were generally lower or similar in EMPA vs. PBO, regardless of predictive baseline factors. EMPA-induced CV death risk reduction was consistent across subgroups below vs. above average eGFR dipping OR (Panel A) and not affected by eGFR dip >10% (Panel B). T2D pts with more advanced kidney disease and/or on diuretic therapy were more likely to experience an eGFR dip >10% with EMPA. EMPA reduced CV death, regardless of an initial eGFR dip >10%. Disclosure S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck & Co., Inc., vTv Therapeutics. B.J. Kraus: Research Support; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH. M.R. Weir: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Scientific Affairs, LLC., Merck & Co., Inc. G. Bakris: Consultant; Self; Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. M. Mattheus: None. D. Cherney: Research Support; Self; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. Other Relationship; Self; from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, Bayer, Prometic, BMS and Novo-Nordisk. N. Sattar: Advisory Panel; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Pfizer Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. I. Ritter: Employee; Self; Boehringer Ingelheim International GmbH. M. von Eynatten: Other Relationship; Self; Boehringer Ingelheim International GmbH. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck & Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker’s Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. A. Koitka-Weber: Employee; Self; Boehringer Ingelheim International GmbH.

Background and Aims Empagliflozin (EMPA) reduces cardiovascular and renal risk in patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD). EMPA induces an initial ‘dip’ in estimated glomerular filtration rate (eGFR). Although considered to be of haemodynamic origin and largely reversible, this needs to be better understood. We investigated whether the initial eGFR dip after EMPA initiation was influenced by baseline characteristics and/or might have an impact on the EMPA-induced risk reduction in kidney outcomes. Method In the EMPA-REG OUTCOME trial, patients with T2D and established CVD were treated (1:1:1) with EMPA 10 mg, 25 mg or placebo (PBO), in addition to standard of care. In this post hoc analysis, 6,668 participants who received at least one dose of study drug and had an available eGFR value at both baseline and Week 4 were categorised by initial percentage eGFR change from baseline. A multivariate logistic regression model was used to identify which baseline characteristics are predictive of an initial eGFR dip >10% in EMPA-treated participants versus PBO. Across these predictive baseline factors, we investigated the occurrence of incident or worsening nephropathy, hard kidney outcomes (defined as doubling of serum creatinine with eGFR [MDRD] ≤45 ml/min/1.73 m2 or initiation of renal replacement therapy or death from renal disease), and kidney safety (narrow standardized MedDRA query acute renal failure). The impact of an eGFR dip >10% on the risk reduction with EMPA for incident or worsening nephropathy was assessed using Cox regression analysis adjusting for such eGFR dip. Results In the EMPA-REG OUTCOME trial cohort, an initial eGFR dip of >10% from baseline at Week 4 occurred in more than twice as many participants on EMPA (28.3%) compared to PBO (13.4%). However, a more pronounced eGFR dip of >30% was uncommon, occurring in only 1.4% and 0.9%, respectively. Within the EMPA group, participants with an eGFR dip >10% were significantly older, had longer diabetes duration and showed a higher KDIGO (Kidney Disease: Improving Global Outcomes) risk category. Diuretic use and/or higher KDIGO risk category at baseline were predictive of an initial eGFR dip of >10% in EMPA vs. PBO. The average odds ratio [OR; 95% CI] for an eGFR dip >10% with EMPA was 2.7 [2.3–3.0]. In subgroups with a dipping odds ratio below vs. above that average, beneficial treatment effects with EMPA on incident or worsening nephropathy and the hard kidney outcome were consistent (panel A). Also, an eGFR dip >10% did not affect risk reduction for the primary kidney outcome (panel B). Acute renal failure rates were generally lower or similar in EMPA vs. PBO, regardless of baseline predictive factors for an eGFR dip. Conclusion T2D patients with more advanced kidney disease and/or on diuretic therapy at baseline were more likely to have an initial eGFR dip >10% with EMPA. However, EMPA treatment appeared to be safe and was associated with improved kidney outcomes, regardless of these baseline predictive factors or an initial eGFR dip >10%.

Introduction EMPA induces an initial decline in estimated glomerular filtration rate (eGFR) in T2D pts. Although considered hemodynamic and reversible, it may raise concerns in clinical practice. This phenomenon needs to be better understood in pts with HF, beyond T2D. Hypothesis To assess eGFR after starting/stopping EMPA in HF pts with/without T2D in the EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and heart failure symptoms In patients with chronic heArt faiLure)-Reduced and -Preserved trials. Methods Pts with HF (NYHA class II-IV, diagnosed ≥3 months prior), baseline eGFR >20 mL/min/1.73 m2, elevated NT-proBNP, and LVEF ≤40% in EMPERIAL-Reduced and >40% in -Preserved, received placebo (PBO) or EMPA 10mg. Overall and across subgroups by baseline T2D status, eGFR changes were analyzed for pooled EMPA (both EMPERIAL trials) vs PBO using a mixed model repeated measures analysis. Acute renal failure (ARF) incidence was assessed by investigator-reported adverse events (AEs) coded according to the narrow standardized MedDRA query. Results EMPERIAL-Reduced and -Preserved included 312 (156 EMPA, 156 PBO) and 315 pts (157 EMPA, 158 PBO), respectively. At baseline in the pooled data set, 55.6% had T2D. Overall, mean baseline eGFR±SD was 57.6±19.3 mL/min/1.73 m2. PBO-adjusted mean eGFR±SE change from baseline with pooled EMPA was -2.3±0.7 and -3.3±0.8 at Weeks 6 and 12, respectively (Figure A). Change in eGFR±SE from last value on treatment to follow-up was -0.3±0.5 in PBO and +3.9±0.5 in EMPA groups (Figure A). These findings were consistent across subgroups by baseline T2D status (Figure B). Incidence rates of ARF were similar in PBO and EMPA groups (n=9 and n=8; 11.8 and 10.7 per 100pt-years, respectively), and also consistent across subgroups by baseline T2D status. Serious ARF occurred in 4 PBO pts and 1 EMPA pt. Conclusions In HF pts with baseline eGFR down to 20 mL/min/1.73 m2, eGFR dynamics after starting/stopping EMPA and kidney AEs were similar to EMPA's known eGFR change on and off treatment, and kidney safety profile, regardless of T2D status.