Fasting and postprandial kidney haemodynamic effects of empagliflozin and linagliptin in mono- and combination therapy compared to gliclazide in overweight people with type 2 diabetes

Background: Sodium-glucose cotransporter (SGLT) 2 inhibitors attenuate fasting glomerular hyperfiltration in people with type 2 diabetes (T2D). However, Sodium-glucosecotransporter 2-inhibition increases glucagon levels, which facilitate postprandial hyperfiltration. The impact of Sodium-glucose cotransporter 2 inhibition on protein-related hyperfiltration and postprandial (intra) kidney haemodynamic function is unclear. Moreover, the interaction with dipeptidylpeptidase (DPP)-4 inhibitors, known to reduce glucagon levels and to affect meal related factors modulating glomerular filtration rate GFR, is unknown. Aims: We aimed to assess the effects of empagliflozin and linagliptin in mono- and combination therapy compared to the initiation and intensification of SU-derivative gliclazide treatment on fasting and postprandial kidney haemodynamic function. Materials and Methods: We compared three 16-week glucose-loweringstrategies added to ongoing metformin monotherapy: (1) EMPA-LINA: 8-week empagliflozin 10 mg QD (EMPA0-8w) followed by the addition of 8-week linagliptin 5 mg QD (LINA8-16w); (2) LINA-EMPA: 8-week linagliptin (LINA0-8w) followed by the addition of 8-week empagliflozin (EMPA8-16w) versus; (3) GLIC-GLIC: 8-week gliclazide 30 mg QD (GLIC0-8w) followed by the addition of 8-week gliclazide 30 mg (GLIC8- 16w). We studied (intra) kidney haemodynamic interactions of this combination using iohexol and PAHclearance techniques to assess measured glomerular filtration rate (mGFR) and effectiverenal plasma flow (ERPF).Results: We studied n = 61 overweight people with type 2 diabetes T2D (HbA1c 62 + 11 mmol/mol, eGFR 89 [78_100] mL/min/1.73 m2 and urinary albumin-creatinine-ratio 1.0 [0.4_1.9] mg/mmol). In the fasting state, 0-8 week empagliflozin EMPA0-8w (−13.2; −21.3 to −5.1 mL/min) but not 0-8 week linagliptin LINA0-8w reduced within-group measured glomerular filtration rate (mGFR). 8-16 week empagliflozin EMPA8-16w (−10.2; −16.5 to −4.0 mL/min) but not 8-16 week linagliptin LINA8-16w reduced within-group measuredglomerular filtration rate (mGFR). Following a proteinload, 0-8 week empagliflozin EMPA0 8w (−11.4; −20.2 to −2.6 mL/min) and 8-16 week empagliflozin EMPA8-16w (−16.2; −22.9 to −9.4 mL/min) but not 0-8 week linagliptin LINA0-8wor 8-16 week linagliptin LINA8-16w reduced within-group measured glomerular filtrationrate (mGFR). Versus the comparatorarm, fasting measured glomerular filtration rate (mGFR) 0-8 week empagliflozin EMPA0-8w, 8-16 week empagliflozin EMPA8-16w and EMPA-LINA and postprandial mGFR EMPA8-16w and LINA-EMPA, were significantly reduced. measured glomerular filtration rate (mGFR)  reductions resulted from intra kidney efferentvasodilation rather than afferent vasoconstriction. Conclusion: In type 2 diabetes people without chronic kidney disease (CKD), the favourablekidney haemodynamic effects of empagliflozin persist in the postprandial state and are irrespective of concurrent use of linagliptin.