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 (RACELINES): A randomised, double-blind trial

Background: Sodium-glucose cotransporter (SGLT) 2 inhibitors attenuate fasting glomerular hyperfiltration in people with type 2 diabetes (T2D). However, SGLT2-inhibition increases glucagon levels, which facilitate postprandial hyperfiltration. The impact of SGLT2 inhibition on protein-related hyperfiltration and postprandial (intra) kidney haemodynamic function is unclear. Moreover, the interaction with dipeptidyl-peptidase (DPP)-4 inhibitors, known to reduce glucagon levels and to affect meal-related factors modulating 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-lowering strategies 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 PAH clearance techniques to assess measured glomerular filtration rate (mGFR) and effective renal plasma flow (ERPF). Results: We studied n = 61 overweight people with 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, EMPA0-8w (−13.2; −21.3 to −5.1 mL/min) but not LINA0-8w reduced within-group mGFR. EMPA8-16w (−10.2; −16.5 to −4.0 mL/min) but not LINA8-16w reduced within-group mGFR. Following a proteinload, EMPA0-8w (−11.4; −20.2 to −2.6 mL/min) and EMPA8-16w (−16.2; −22.9 to −9.4 mL/min) but not LINA0-8w or LINA8-16w reduced within-group mGFR. Versus the comparatorarm, fasting mGFR EMPA0-8w, EMPA8-16w and EMPA-LINA and postprandial mGFR EMPA8-16w and LINA-EMPA, were significantly reduced. mGFR reductions resulted from intrakidney efferent vasodilation rather than afferent vasoconstriction. Conclusion: In T2D people without CKD, the favourable kidney haemodynamic effects of empagliflozin persist in the postprandial state and are irrespective of concurrent use of linagliptin.