Analysis from the EMPA-REG OUTCOME® trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics
Authors: Gert J. Mayer, Christoph Wanner, Matthew R. Weir, Silvio E. Inzucchi, Audrey Koitka-Weber, Stefan Hantel, Maximilian von Eynatten, Bernard Zinman, David Z.I. Cherney
Journal: Kidney International (2019)

In patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease, empagliflozin (EMPA) decreased progression of chronic kidney disease (CKD), likely via a reduction in intraglomerular pressure. Due to prevalent comorbidities, such as hypertension and albuminuria, patients often receive other agents that alter intrarenal hemodynamics, including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), calcium channel blockers (CCBs) and diuretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used by some individuals. In this exploratory, non-prespecified analysis, we investigated whether the kidney benefits of EMPA are altered in individuals already using the medications in these categories. In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, 7020 patients were essentially equally randomized to EMPA 10 mg, 25 mg or placebo added to their standard care. Differences in risk of incident or worsening nephropathy for pooled EMPA vs placebo across subgroups by baseline background medications (to which patients were not randomized) were assessed using a Cox proportional hazards model. Risk reductions in incident or worsening nephropathy with EMPA were consistent across medication subgroups, with no heterogeneity of treatment effect. As a representative example, the risk for acute renal failure was overall slightly increased in patients using ACEi/ARBs in all groups (placebo, EMPA 10 mg or EMPA 25 mg) but incidence rates were numerically lower in those assigned to EMPA. Similar patterns were observed for other medications included in this analysis. Thus, EMPA may assist to prevent CKD progression in patients with T2DM with CV disease, irrespective of common background medications that alter intrarenal hemodynamics, and without increasing acute renal adverse events. In patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease, empagliflozin (EMPA) decreased progression of chronic kidney disease (CKD), likely via a reduction in intraglomerular pressure. Due to prevalent comorbidities, such as hypertension and albuminuria, patients often receive other agents that alter intrarenal hemodynamics, including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), calcium channel blockers (CCBs) and diuretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used by some individuals. In this exploratory, non-prespecified analysis, we investigated whether the kidney benefits of EMPA are altered in individuals already using the medications in these categories. In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, 7020 patients were essentially equally randomized to EMPA 10 mg, 25 mg or placebo added to their standard care. Differences in risk of incident or worsening nephropathy for pooled EMPA vs placebo across subgroups by baseline background medications (to which patients were not randomized) were assessed using a Cox proportional hazards model. Risk reductions in incident or worsening nephropathy with EMPA were consistent across medication subgroups, with no heterogeneity of treatment effect. As a representative example, the risk for acute renal failure was overall slightly increased in patients using ACEi/ARBs in all groups (placebo, EMPA 10 mg or EMPA 25 mg) but incidence rates were numerically lower in those assigned to EMPA. Similar patterns were observed for other medications included in this analysis. Thus, EMPA may assist to prevent CKD progression in patients with T2DM with CV disease, irrespective of common background medications that alter intrarenal hemodynamics, and without increasing acute renal adverse events. In this issueKidney InternationalVol. 96Issue 2PreviewEmpagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was shown to attenuate cardiovascular and renal morbidity in patients with type 2 diabetes in the EMPA-REG Outcome trial. EMPA decreased the risk of incident or worsening nephropathy, progression to macroalbuminuria, and the combined endpoint of doubling of serum creatinine and need for renal replacement therapy. This is due, in part, to a reduction in glomerular hypertension. Mayer and colleagues wondered whether EMPA was still effective in patients taking commonly used background medications that also affect glomerular hemodynamics. Full-Text PDF SGLT2 inhibitors' interaction with other renoactive drugs in type 2 diabetes patients: still a lot to learnKidney InternationalVol. 96Issue 2PreviewThe first cardiovascular (CV) safety trial conducted with a sodium-glucose cotransporter (SGLT)-2 inhibitor, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients—Removing Excess Glucose (EMPA-REG OUTCOME), reported not only remarkable risk reductions in CV outcome, but also impressive improvements in renal outcome. Changes in renal hemodynamics could be involved in the benefit of SGLT2 inhibitors on renal outcomes. Considering that all patients of EMPA-REG OUTCOME had established atherosclerotic CV disease at baseline, many patients were also treated with several CV drugs at baseline, including RAS blockers, diuretics, calcium-channel blockers, and nonsteroidal anti-inflammatory drugs. Full-Text PDF The authors replyKidney InternationalVol. 97Issue 1PreviewIn their letter, León-Jiménez et al.1 argue that in the Dapagliflozin Effect on Cardiovascular Events Thrombolysis in Myocardial Infarction 58 (DECLARE TIMI 58) trial,2 participants treated with dapagliflozin but who did not take background diuretic therapies at baseline had the greatest benefits in the composite cardiorenal outcomes. While the trends in the point estimates suggest such a possible interaction, a formal statistical inquiry actually indicates none (P value for interaction of 0.13). Full-Text PDF Is the joint use of diuretics and SGLT2 inhibitors beneficial in diabetic kidney disease?Kidney InternationalVol. 97Issue 1PreviewWe read the article published in the Journal by Mayer et al.1 with interest. The authors concluded that there was no interaction between drugs that could alter glomerular hemodynamics and empagliflozin, in relation to renal end points. Full-Text PDF