目的:已提出从扩散加权MRI(DWI-MRI)得出的表观扩散系数(ADC)作为肾脏微观结构变化的量度,包括肾纤维化.在晚期肾病中,肾脏经常萎缩;然而,在2型糖尿病的初始阶段,肾脏大小增加。胰高血糖素样肽-1受体激动剂和钠-葡萄糖协同转运蛋白2抑制剂均为糖尿病肾病的发展提供保护。然而,机制还没有完全理解。为了探索这个,我们研究了司马鲁肽的作用,依帕利列净及其组合对肾脏ADC和总肾脏体积(TKV)的影响。
方法:这是一项关于司马鲁肽和依帕列净单独或联合使用效果的随机临床试验的亚研究。80例2型糖尿病和心血管疾病高风险患者被随机分为四组(每组20例),分别接受片剂安慰剂,empagliflozin,司马鲁肽和片剂安慰剂的组合(本文称为“司马鲁肽”组),或司马鲁肽和依帕列净的组合(称为“联合治疗”组)。司马鲁肽和联合治疗组接受司马鲁肽治疗16周,然后在治疗中加入片剂安慰剂或依帕格列净,分别,再治疗16周;安慰剂组和依帕列净组分别接受单药治疗32周.我们分析了治疗对ADC变化的影响(皮质,髓质和皮质髓质差异[ΔADC;从皮质ADC中减去髓质ADC]),以及MRI测量的TKV。
结果:与安慰剂相比,塞马鲁肽和依帕列净均显着降低皮质ADC(塞马鲁肽:-0.20×10-3mm2/s[95%CI-0.30,-0.10],p<0.001;依帕列净:-0.15×10-3mm2/s[95%CI-0.26,-0.04],p=0.01)。联合治疗组未观察到显著变化(-0.05×10-3mm2/s[95CI-0.15,0.05];与安慰剂组相比,p=0.29)。皮质ADC的变化与GFR的变化无关,白蛋白尿,TKV或炎症标志物。Further,与安慰剂组相比,任何组的髓质ADC均无变化.只有司马鲁肽治疗与安慰剂相比显著改变了ΔADC,显示减少-0.13×10-3mm2/s(95%CI-0.22,-0.04;p=0.01)。与安慰剂相比,TKV下降-3%(95%CI-5%,-0.3%;p=0.04),-3%(95%CI-5%,-0.4%;p=0.02)和-5%(95%CI-8%,-2%;p<0.001)在司马鲁肽中,empagliflozin和联合治疗组,分别。TKV的变化与GFR的变化有关,白蛋白尿和HbA1c。
结论:在2型糖尿病和心血管疾病高风险人群中,与安慰剂相比,塞马鲁肽和依帕列净显着降低皮质ADC,表明肾脏的微观结构变化。这些变化与GFR的变化无关,白蛋白尿或炎症。Further,我们发现所有活性治疗组的TKV下降,这可能是由超滤减少介导的。我们的研究结果表明,DWI-MRI可能是研究2型糖尿病患者医疗干预的潜在机制的有希望的工具,但可能反映了与纤维化无关的影响。
背景:欧盟药物监管机构临床试验数据库(EudraCT)2019-000781-38。
OBJECTIVE: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV).
METHODS: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the \'semaglutide\' group), or the combination of semaglutide and empagliflozin (referred to as the \'combination-therapy\' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI.
RESULTS: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10-3 mm2/s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10-3 mm2/s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10-3 mm2/s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10-3 mm2/s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c.
CONCLUSIONS: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis.
BACKGROUND: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38.