van Baar Michaël J B, Muskiet Marcel H A, Scholtes Rosalie A, Touw Daan J, Nieuwdorp Max, Kramer Mark H H, Joles Jaap A, Cherney David Z I, Bjornstad Petter, Krebber Merle M, van Raalte Daniël H
Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands.
Diabetes Obes Metab. 2025 Jul;27(7):3943-3956. doi: 10.1111/dom.16431. Epub 2025 May 6.
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.
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.
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).
We studied n = 61 overweight people with T2D (HbA1c 62 + 11 mmol/mol, eGFR 89 [78-100] mL/min/1.73 m 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.
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.
钠-葡萄糖协同转运蛋白（SGLT）2抑制剂可减轻2型糖尿病（T2D）患者的空腹肾小球高滤过。然而，SGLT2抑制会增加胰高血糖素水平，从而促进餐后高滤过。SGLT2抑制对蛋白质相关高滤过及餐后（肾内）肾脏血流动力学功能的影响尚不清楚。此外，与已知可降低胰高血糖素水平并影响调节肾小球滤过率（GFR）的进餐相关因素的二肽基肽酶（DPP）-4抑制剂之间的相互作用也未知。
我们旨在评估与启动和强化磺脲类衍生物格列齐特治疗相比，恩格列净和利格列汀单药及联合治疗对空腹和餐后肾脏血流动力学功能的影响。
我们比较了在正在进行的二甲双胍单药治疗基础上加用的三种为期16周的降糖策略：（1）EMPA-LINA：8周恩格列净10mg每日一次（EMPA0-8周），随后加用8周利格列汀5mg每日一次（LINA8-16周）；（2）LINA-EMPA：8周利格列汀（LINA0-8周），随后加用8周恩格列净（EMPA8-16周），与（Ⅲ）GLIC-GLIC：8周格列齐特30mg每日一次（GLIC0-8周），随后加用8周格列齐特30mg（GLIC8-16周）。我们使用碘海醇和对氨基马尿酸清除技术研究了这种联合治疗的（肾内）肾脏血流动力学相互作用，以评估实测肾小球滤过率（mGFR）和有效肾血浆流量（ERPF）。
我们研究了n = 61例超重的T2D患者（糖化血红蛋白62 + 11mmol/mol，估算肾小球滤过率89[78 - 100]mL/min/1.73m²，尿白蛋白-肌酐比值1.0[0.4 - 1.9]mg/mmol）。在空腹状态下，EMPA0-8周（-13.2；-21.3至-5.1mL/min）可降低组内mGFR，而LINA0-8周则不能。EMPA8-16周（-10.2；-16.5至-4.0mL/min）可降低组内mGFR，而LINA8-16周则不能。摄入蛋白质后，EMPA0-8周（-11.4；-20.2至-2.6mL/min）和EMPA8-16周（-16.2；-22.9至-9.4mL/min）可降低组内mGFR，而LINA0-8周或LINA8-16周则不能。与对照臂相比，空腹mGFR在EMPA0-8周EMPA8-16周和EMPA-LINA组，以及餐后mGFR在EMPA8-16周和LINA-EMPA组均显著降低。mGFR降低是由肾内出球小动脉舒张而非入球小动脉收缩所致。
在无慢性肾脏病的T2D患者中，恩格列净对肾脏血流动力学的有益作用在餐后状态持续存在，且与同时使用利格列汀无关。
