Nandula Seshagiri Rao, Jain Arad, Sen Sabyasachi
Department of Medicine, Veterans Affairs Medical Center, Washington, DC, USA.
Department of Medicine, George Washington University, Washington, DC, USA.
Stem Cell Res Ther. 2025 Jan 26;16(1):28. doi: 10.1186/s13287-025-04130-x.
Effects of Dapagliflozin (Dapa) and Dapagliflozin-Saxagliptin combination (Combo) was examined on peripheral blood derived CD34 + Hematopoetic Stem Cells (HSCs) as a cellular CVD biomarker. Both Dapa (a sodium-glucose co-transporter 2 or SGLT2, receptor inhibitor) and Saxagliptin (a Di-peptydl-peptidase-4 or DPP4 enzyme inhibitor) are commonly used type 2 diabetes mellitus or T2DM medications, however the benefit of using the combination has not been evaluated for cardio-renal risk assessment, in a real-life practice setting, compared to a placebo.
We hypothesized that Dapa will improve the outcomes when compared to placebo and the Combo maybe even more beneficial.
This is a pilot study evaluating low dose Dapagliflozin 10 mg or low dose Dapa + low dose Saxagliptin combination. 15 subjects were enrolled in 16 weeks, double-blind, three-arm, randomized placebo matched trial, with 10mg Dapa + Saxa placebo (n = 4), 10 mg Dapa + 5 mg Saxa (n = 5) Combo, And Dapa placebo + Saxa placebo (n = 6), Placebo groups. T2DM subjects (age 30-70 yrs) with HbA1c of 7-10%, were included. CD34 + HSC number, migration, mRNA expression along with biochemistry and urine exosomes were measured. Data were collected at week 0, 8, and 16. For statistics, a mixed model regression analysis was used.
Significant HbA1c (p = 0.0357) reduction was noted in Combo group versus Dapa alone and Placebo. hsCRP levels (P = 0.0317) and IL-6, two important inflammatory molecules, were significantly reduced in both Dapa and Combo vs. Placebo. Leptin levels decreased significantly in both Dapa alone (p = 0.035) and Combo group(p = 0.015), vs. Placebo, however the Adiponectin levels were higher in Dapa alone group. Dapagliflozin alone reduced lipid parameters significantly particularly triglyceride (TG) when compared to placebo, with resultant visit 3 values at 99.5 ± 7.2 vs. 129 ± 12.3 and LDL/HDL ratio values were similar at 2.18 ± 0.08 vs. 2.13 ± 0.15. CD34 + cell migration improved significantly in both Dapa alone (p = 0.05) and Combo group (p = 0.05) vs. Placebo.
Several parameters showed significant improvement with both Dapa alone and Combo compared to placebo. However, when all outcome measures were taken into account, other than glycemic control the Combo didn't seem to offer any further benefit, over Dapa alone. Therefore, contrary to our initial hypothesis we do not believe the more expensive Dapa + Saxa combination offers any specific cardiovascular benefit compared to Dapagliflozin alone. However it is noteworthy that both Dapa and its combination with Saxagliptin showed significant improvement compared to placebo in T2DM, particularly when progenitor cell based numbers and function were analyzed and taken into account.
The trial was registered with Clinical Trials.gov number NCT03660683, last updated 06052023.
研究了达格列净（Dapa）及达格列净与沙格列汀联合用药（Combo）对外周血来源的CD34+造血干细胞（HSCs）的影响，将其作为一种细胞性心血管疾病生物标志物。Dapa（一种钠-葡萄糖协同转运蛋白2即SGLT2受体抑制剂）和沙格列汀（一种二肽基肽酶4即DPP4酶抑制剂）均为常用的2型糖尿病（T2DM）药物，然而，在实际临床实践中，与安慰剂相比，联合用药对心肾风险评估的益处尚未得到评估。
我们假设与安慰剂相比，Dapa将改善预后，且联合用药可能更有益。
这是一项评估低剂量达格列净10mg或低剂量Dapa与低剂量沙格列汀联合用药的试点研究。15名受试者参加了为期16周的双盲、三臂、随机安慰剂对照试验，分为10mg Dapa+沙格列汀安慰剂组（n = 4）、10mg Dapa + 5mg沙格列汀（n = 5）联合用药组以及Dapa安慰剂+沙格列汀安慰剂组（n = 6）即安慰剂组。纳入糖化血红蛋白（HbA1c）为7 - 10%的30 - 70岁T2DM患者。测量CD34+HSC数量、迁移、mRNA表达以及生化指标和尿液外泌体。在第0、8和16周收集数据。统计分析采用混合模型回归分析。
与单独使用Dapa组和安慰剂组相比，联合用药组的HbA1c显著降低（p = 0.0357）。与安慰剂组相比，Dapa组和联合用药组的超敏C反应蛋白（hsCRP）水平（P = 0.0317）以及两种重要的炎症分子白细胞介素6均显著降低。与安慰剂组相比，单独使用Dapa组（p = 0.035）和联合用药组（p = 0.015）的瘦素水平均显著降低，然而单独使用Dapa组的脂联素水平更高。与安慰剂相比，单独使用达格列净显著降低了血脂参数，尤其是甘油三酯（TG），第3次随访时TG值为99.5±7.2，而安慰剂组为129±12.3，低密度脂蛋白/高密度脂蛋白比值相似，分别为2.18±0.08和2.13±0.15。与安慰剂组相比，单独使用Dapa组（p = 0.05）和联合用药组（p = 0.05）的CD34+细胞迁移均显著改善。
与安慰剂相比，单独使用Dapa和联合用药在多个参数上均显示出显著改善。然而，综合所有结局指标来看，除血糖控制外，联合用药组相较于单独使用Dapa组似乎并未提供更多益处。因此，与我们最初的假设相反，我们认为与单独使用达格列净相比，更昂贵的Dapa + 沙格列汀联合用药并未提供任何特定的心血管益处。然而值得注意的是，与安慰剂相比，Dapa及其与沙格列汀的联合用药在T2DM患者中均显示出显著改善，特别是在分析和考虑基于祖细胞的数量和功能时。
该试验已在ClinicalTrials.gov注册，注册号为NCT03660683，最后更新于2023年5月6日。
