Renal hemodynamic effects differ between antidiabetic combination strategies: randomized controlled clinical trial comparing empagliflozin/linagliptin with metformin/insulin glargine

Abstract

Background Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail. Methods Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model. Results Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both padjust < 0.001). Analysis of intraglomerular hemodynamics revealed that E+L did not change resistance of afferent arteriole (RA) (p = 0.116), but diminished resistance of efferent arterioles (RE) (p = 0.001). In M+I group RA was increased (p = 0.006) and RE remained unchanged (p = 0.538). The effects on RA (padjust < 0.05) and on RE (padjust < 0.05) differed between the groups. Conclusions In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing RA and E+L predominantly decreasing RE, which is in contrast to the proposed sodium-glucose cotransporter 2 inhibitor effects. Trial registration: The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016

Albuminuria‐lowering effect of dapagliflozin, exenatide, and their combination in patients with type 2 diabetes: A randomized cross‐over clinical study

“…An initial decline in eGFR is a well‐known phenomenon after starting an SGLT2 inhibitor and the observed effects in the present trial are consistent with previous studies 28,29 . The mechanisms by how SGLT2 inhibitors modulate renal haemodynamics are not completely understood, but studies in patients with type 2 diabetes and preserved kidney function have suggested that dilation of postglomerular arterioles are probably involved in the haemodynamic effects of SGLT2 inhibitors 27,30,31 . Emerging data suggest that SGLT2 inhibitors can both constrict afferent arterioles and dilate efferent arterioles 27,30 .…”

“…28,29 The mechanisms by how SGLT2 inhibitors modulate renal haemodynamics are not completely understood, but studies in patients with type 2 diabetes and preserved kidney function have suggested that dilation of postglomerular arterioles are probably involved in the haemodynamic effects of SGLT2 inhibitors. 27,30,31 Emerging data suggest that SGLT2 inhibitors can both constrict afferent arterioles and dilate efferent arterioles. 27,30 However, it should be noted that efferent postglomerular arterioles have smaller diameters than preglomerular arterioles.…”

Angiotensin pathways under therapy with empagliflozin in patients with chronic heart failure

“…Large outcome trials in patients with CHF demonstrate that there are no additional safety findings in patients treated with SGLT2 inhibitors and RAS inhibitors. 1 , 2 , 20 Previous studies in patients with T2DM suggest that SGLT2 inhibitors exert part of their beneficial effects via post‐glomerular vasodilation, 21 , 22 , 23 which is also one major nephroprotective action of ACEI/ARBs. Combining these two drug classes therefore possibly has an additive effect regarding renal haemodynamic function.…”

SGLT2 Inhibitors in the Treatment of Diabetic Kidney Disease: More than Just Glucose Regulation

“…The conventional treatments to maintain blood glucose levels do not always prevent DKD [ 13 ]. On the other hand, it was reported that sodium–glucose cotransporter-2 (SGLT2) inhibitors, which are quite novel but already a widely used therapy, may prevent the development and alter the natural progression of DKD by inducing systemic and glomerular hemodynamic changes, providing metabolic advantages, and diminishing inflammatory and oxidative stress pathways [ 1 , 14 , 15 , 16 , 17 ], which we have shown in the Figure 1 .…”