Fenofibrate increases circulating haematopoietic stem cells in people with diabetic retinopathy: a randomised, placebo-controlled trial,Diabetologia

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Fenofibrate increases circulating haematopoietic stem cells in people with diabetic retinopathy: a randomised, placebo-controlled trial
Diabetologia ( IF 8.4 ) Pub Date : 2021-08-09 , DOI: 10.1007/s00125-021-05532-1
Benedetta Maria Bonora _{1,

2} , Mattia Albiero _{1,

2} , Mario Luca Morieri ₁ , Roberta Cappellari ₁ , Francesco Ivan Amendolagine ₂ , Marta Mazzucato ₁ , Alberto Zambon ₁ , Elisabetta Iori ₁ , Angelo Avogaro ₁ , Gian Paolo Fadini _{1,

2}

Affiliation

Aim/hypothesis

In two large RCTs, fenofibrate reduced the progression of diabetic retinopathy. We investigated whether fenofibrate increases circulating haematopoietic stem/progenitor cells (HSPCs), which have vascular properties and have been shown to protect from retinopathy.

Methods

We conducted a 12 week parallel-group RCT comparing fenofibrate vs placebo. Patients with diabetic retinopathy and without other conditions that would affect HSPCs were enrolled at a tertiary diabetes outpatient clinic and randomised to receive fenofibrate or placebo based on a computer-generated sequence. Patients and study staff assessing the outcomes were blinded to group assignment. The primary endpoint was the change in the levels of circulating HSPCs, defined by expression of the stem cell markers CD34 and/or CD133. Secondary endpoints were the changes in endothelial progenitor cells, lipids, soluble mediators and gene expression. We used historical data on the association between HSPCs and retinopathy outcomes to estimate the effect of fenofibrate on retinopathy progression.

Results

Forty-two participants with diabetic retinopathy were randomised and 41 completed treatment and were analysed (20 in the placebo group and 21 in the fenofibrate group). Mean age was 57.4 years, diabetes duration was 18.2 years and baseline HbA_1c was 60 mmol/mol (7.6%). When compared with placebo, fenofibrate significantly increased levels of HSPCs expressing CD34 and/or CD133. CD34⁺ HSPCs non-significantly declined in the placebo group (mean ± SD –44.2 ± 31.6 cells/10⁶) and significantly increased in the fenofibrate group (53.8 ± 31.1 cells/10⁶). The placebo-subtracted increase in CD34⁺ HSPCs from baseline was 30% (99.3 ± 43.3 cells/10⁶; p = 0.027) which, projected onto the relationship between HSPC levels and retinopathy outcomes, yielded an OR of retinopathy progression of 0.67 for fenofibrate vs placebo. Endothelial differentiation of CD34⁺ cells, estimated by the %KDR (kinase insert domain receptor) expression, was significantly reduced by fenofibrate. Fenofibrate decreased serum triacylglycerols, but the change in triacylglycerols was unrelated to the change in HSPCs. No effect was observed for endothelial progenitor cells, cytokines/chemokines (stromal-cell derived factor-1, vascular endothelial growth factor, monocyte chemoattractant protein-1) and gene expression in peripheral blood mononuclear cells.

Conclusions/interpretation

Fenofibrate increased HSPC levels in participants with diabetic retinopathy and this mechanism may explain why fenofibrate reduced retinopathy progression in previous studies.

Trial registration

ClinicalTrials.gov NCT01927315.

Graphical abstract

中文翻译：

非诺贝特增加糖尿病视网膜病变患者的循环造血干细胞：一项随机、安慰剂对照试验

目标/假设

在两项大型 RCT 中，非诺贝特减缓了糖尿病视网膜病变的进展。我们研究了非诺贝特是否会增加循环造血干/祖细胞 (HSPC)，这些细胞具有血管特性并已被证明可以防止视网膜病变。

方法

我们进行了一项为期 12 周的平行组 RCT，比较了非诺贝特与安慰剂。患有糖尿病视网膜病变且没有其他会影响 HSPC 的疾病的患者被纳入三级糖尿病门诊，并根据计算机生成的序列随机接受非诺贝特或安慰剂。评估结果的患者和研究人员对分组不知情。主要终点是循环 HSPCs 水平的变化，由干细胞标志物 CD34 和/或 CD133 的表达定义。次要终点是内皮祖细胞、脂质、可溶性介质和基因表达的变化。我们使用 HSPCs 与视网膜病变结果之间关联的历史数据来估计非诺贝特对视网膜病变进展的影响。

结果

42 名患有糖尿病性视网膜病变的参与者被随机分配，其中 41 名完成了治疗并进行了分析（安慰剂组 20 名，非诺贝特组 21 名）。平均年龄为 57.4 岁，糖尿病病程为 18.2 岁，基线 HbA _1c为 60 mmol/mol (7.6%)。与安慰剂相比，非诺贝特显着增加表达 CD34 和/或 CD133 的 HSPC 水平。CD34 ⁺ HSPCs 在安慰剂组中没有显着下降（平均值 ± SD –44.2 ± 31.6 个细胞/10 ⁶），而在非诺贝特组中显着增加（53.8 ± 31.1 个细胞/10 ⁶）。^{CD34 +} HSPCs 从基线减去安慰剂后的增加为 30%（99.3 ± 43.3 个细胞/10 ⁶；p = 0.027），根据 HSPC 水平和视网膜病变结果之间的关系，非诺贝特与安慰剂的视网膜病变进展 OR 为 0.67。由 %KDR（激酶插入结构域受体）表达估计的 CD34 ⁺细胞的内皮分化被非诺贝特显着降低。非诺贝特降低血清甘油三酯，但甘油三酯的变化与HSPCs的变化无关。未观察到内皮祖细胞、细胞因子/趋化因子（基质细胞衍生因子-1、血管内皮生长因子、单核细胞趋化蛋白-1）和外周血单核细胞中的基因表达有影响。