Abstract：
Glucagon-like peptide-1 receptor agonists (GLP-1ras) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown kidney-protective effects. Improved kidney oxygenation and haemodynamic changes are suggested mechanisms; however, human data are scarce. We therefore investigated whether semaglutide (GLP-1ra), empagliflozin (SGLT2i) or their combination improve kidney oxygenation and perfusion.
The trial was undertaken at Aarhus University Hospital, Denmark. A total of 120 people with type 2 diabetes (HbA1c ≥48 mmol/mol [6.5%]) and at high risk of CVD (age ≥50 years) were randomised into four parallel groups (n=30 in each group) for 32 weeks: 1.0 mg semaglutide (open label); 10 mg empagliflozin (blinded to participants, caregivers, examiners and outcome assessors); their combination (1.0 mg semaglutide open label plus 10 mg empagliflozin blinded to participants, caregivers, examiners and outcome assessors); and placebo tablet (blinded to participants, caregivers, examiners and outcome assessors). Sequentially numbered, sealed envelopes containing computer-generated randomisation codes, provided by Glostrup Pharmacy, Glostrup, Denmark, determined the intervention. The two co-primary outcomes were change in kidney oxygenation and change in arterial stiffness. This paper reports on kidney oxygenation, for which 80 individuals as prespecified, 20 in each group, underwent MRI. We primarily hypothesised that kidney oxygenation would be improved in the active treatment groups compared with placebo after 32 weeks. Secondary outcomes included changes in kidney perfusion, erythropoietin, haematocrit, urine albumin/creatinine ratio (UACR) and GFR (measured using technetium-99m) compared with baseline and between treatment groups at week 32.
Our model estimated a common baseline R2* value across all four groups in the cortex and the medulla. At baseline, the value was 24.5 (95% CI 23.9, 24.9) Hz in the medulla. After 32 weeks, the R2* values in the medulla were estimated to be 25.4 (95% CI 24.7, 26.2) Hz in the empagliflozin group and 24.5 (95% CI 23.9, 25.1) Hz in the placebo group (p=0.016) (higher R2* corresponds to a lower oxygenation). Semaglutide decreased perfusion in both the cortex and the medulla. Empagliflozin increased erythropoietin and haematocrit. All three active treatments decreased GFR but not UACR. Ten serious adverse events were reported, among them two occurrences of semaglutide-associated obstipation.
Our hypothesis, that semaglutide, empagliflozin or their combination improve kidney oxygenation, was rejected. On the contrary, empagliflozin induced a reduction in medullary kidney oxygenation. Semaglutide substantially reduced kidney perfusion without affecting oxygenation.
Clinicaltrialsregister.eu EudraCT 2019-000781-38 FUNDING: Novo Nordisk Foundation, Central Denmark Region Research Fund and Danish Medical Associations Research Foundation.
The trial was undertaken at Aarhus University Hospital, Denmark. A total of 120 people with type 2 diabetes (HbA1c ≥48 mmol/mol [6.5%]) and at high risk of CVD (age ≥50 years) were randomised into four parallel groups (n=30 in each group) for 32 weeks: 1.0 mg semaglutide (open label); 10 mg empagliflozin (blinded to participants, caregivers, examiners and outcome assessors); their combination (1.0 mg semaglutide open label plus 10 mg empagliflozin blinded to participants, caregivers, examiners and outcome assessors); and placebo tablet (blinded to participants, caregivers, examiners and outcome assessors). Sequentially numbered, sealed envelopes containing computer-generated randomisation codes, provided by Glostrup Pharmacy, Glostrup, Denmark, determined the intervention. The two co-primary outcomes were change in kidney oxygenation and change in arterial stiffness. This paper reports on kidney oxygenation, for which 80 individuals as prespecified, 20 in each group, underwent MRI. We primarily hypothesised that kidney oxygenation would be improved in the active treatment groups compared with placebo after 32 weeks. Secondary outcomes included changes in kidney perfusion, erythropoietin, haematocrit, urine albumin/creatinine ratio (UACR) and GFR (measured using technetium-99m) compared with baseline and between treatment groups at week 32.
Our model estimated a common baseline R2* value across all four groups in the cortex and the medulla. At baseline, the value was 24.5 (95% CI 23.9, 24.9) Hz in the medulla. After 32 weeks, the R2* values in the medulla were estimated to be 25.4 (95% CI 24.7, 26.2) Hz in the empagliflozin group and 24.5 (95% CI 23.9, 25.1) Hz in the placebo group (p=0.016) (higher R2* corresponds to a lower oxygenation). Semaglutide decreased perfusion in both the cortex and the medulla. Empagliflozin increased erythropoietin and haematocrit. All three active treatments decreased GFR but not UACR. Ten serious adverse events were reported, among them two occurrences of semaglutide-associated obstipation.
Our hypothesis, that semaglutide, empagliflozin or their combination improve kidney oxygenation, was rejected. On the contrary, empagliflozin induced a reduction in medullary kidney oxygenation. Semaglutide substantially reduced kidney perfusion without affecting oxygenation.
Clinicaltrialsregister.eu EudraCT 2019-000781-38 FUNDING: Novo Nordisk Foundation, Central Denmark Region Research Fund and Danish Medical Associations Research Foundation.
摘要：
目的：胰高血糖素样肽-1受体激动剂（GLP-1ras）和钠-葡萄糖协同转运蛋白2抑制剂（SGLT2is）已显示出肾脏保护作用。改善肾脏氧合和血液动力学变化被认为是机制；然而，人类数据很少。因此，我们调查了司马鲁肽(GLP-1ra)是否，依帕列净（SGLT2i）或其组合可改善肾脏氧合和灌注。
方法：试验在奥胡斯大学医院进行，丹麦。将120名2型糖尿病患者（HbA1c≥48mmol/mol[6.5%]）和心血管疾病高危人群（年龄≥50岁）随机分为4个平行组（每组30例），共32周：1.0mg司马鲁肽（开放标签）；10mg依帕列净（参与者不知情，看护者,审查员和结果评估员）；他们的组合（1.0mg司马鲁肽开放标签加10mgempagliflozin对参与者不知情，看护者,审查员和结果评估员)；和安慰剂片(对参与者视而不见，看护者,审查员和结果评估员)。按顺序编号，包含计算机生成的随机代码的密封信封，由GlostrupPharmacy提供，Glostrup,丹麦,决定干预。两个共同的主要结果是肾脏氧合的变化和动脉僵硬度的变化。本文报道了肾脏氧合，预定的80个人，每组20人,接受MRI检查。我们主要假设在32周后，与安慰剂相比，活性治疗组的肾脏氧合将得到改善。次要结果包括肾脏灌注的变化，促红细胞生成素,血细胞比容,尿白蛋白/肌酐比值（UACR）和GFR（使用tech-99m测量）与基线和第32周治疗组之间的比较。
结果：我们的模型估计了皮质和髓质四组的共同基线R2*值。在基线,延髓的数值为24.5(95%CI23.9,24.9)Hz.32周后,在依帕列净组,髓质的R2*值估计为25.4(95%CI24.7,26.2)Hz,在安慰剂组(p=0.016)为24.5(95%CI23.9,25.1)Hz(P=0.016)(较高的R2*对应较低的氧合).塞马鲁肽降低了皮质和髓质的灌注。Empagliflozin增加促红细胞生成素和血细胞比容。所有三种活性治疗均降低了GFR，但未降低UACR。报告了10起严重不良事件，其中2例出现司马鲁肽相关性便秘。
结论：我们的假设，那个semaglutide,empagliflozin或其组合改善肾脏氧合，被拒绝了。相反,依帕列净诱导髓样肾氧合减少。塞马鲁肽显著减少肾脏灌注而不影响氧合。
背景：临床试验注册。欧盟EudraCT2019-000781-38资金：诺和诺德基金会，丹麦中部地区研究基金和丹麦医学协会研究基金会。
方法：试验在奥胡斯大学医院进行，丹麦。将120名2型糖尿病患者（HbA1c≥48mmol/mol[6.5%]）和心血管疾病高危人群（年龄≥50岁）随机分为4个平行组（每组30例），共32周：1.0mg司马鲁肽（开放标签）；10mg依帕列净（参与者不知情，看护者,审查员和结果评估员）；他们的组合（1.0mg司马鲁肽开放标签加10mgempagliflozin对参与者不知情，看护者,审查员和结果评估员)；和安慰剂片(对参与者视而不见，看护者,审查员和结果评估员)。按顺序编号，包含计算机生成的随机代码的密封信封，由GlostrupPharmacy提供，Glostrup,丹麦,决定干预。两个共同的主要结果是肾脏氧合的变化和动脉僵硬度的变化。本文报道了肾脏氧合，预定的80个人，每组20人,接受MRI检查。我们主要假设在32周后，与安慰剂相比，活性治疗组的肾脏氧合将得到改善。次要结果包括肾脏灌注的变化，促红细胞生成素,血细胞比容,尿白蛋白/肌酐比值（UACR）和GFR（使用tech-99m测量）与基线和第32周治疗组之间的比较。
结果：我们的模型估计了皮质和髓质四组的共同基线R2*值。在基线,延髓的数值为24.5(95%CI23.9,24.9)Hz.32周后,在依帕列净组,髓质的R2*值估计为25.4(95%CI24.7,26.2)Hz,在安慰剂组(p=0.016)为24.5(95%CI23.9,25.1)Hz(P=0.016)(较高的R2*对应较低的氧合).塞马鲁肽降低了皮质和髓质的灌注。Empagliflozin增加促红细胞生成素和血细胞比容。所有三种活性治疗均降低了GFR，但未降低UACR。报告了10起严重不良事件，其中2例出现司马鲁肽相关性便秘。
结论：我们的假设，那个semaglutide,empagliflozin或其组合改善肾脏氧合，被拒绝了。相反,依帕列净诱导髓样肾氧合减少。塞马鲁肽显著减少肾脏灌注而不影响氧合。
背景：临床试验注册。欧盟EudraCT2019-000781-38资金：诺和诺德基金会，丹麦中部地区研究基金和丹麦医学协会研究基金会。
