Canagliflozin impedes ischemic hind-limb recovery in the setting of diabetes.
Canagliflozin impedes ischemic hind-limb recovery in the setting of diabetes.
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DOI：
10.1177/1358863x20961153
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Zayed MA
中科院分区：
文献类型：
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作者：
Nalugo M;Harroun N;Li C;Belaygorod L;Semenkovich CF;Zayed MA
据报告，在接受卡格列净（一种SGLT 2受体抑制剂）治疗的糖尿病患者中，下肢截肢的发生率增加。目前尚不清楚这是否是治疗的非预期后果，或者卡格列净是否会影响基础动脉灌注不良背景下的外周肢体灌注。为了评价这一点，我们探索了卡格列净对单侧后肢缺血（HLI）后组织恢复的影响。成年野生型（+/+）和糖尿病（db/db）小鼠维持8周的常规饲料或含卡格列净（200 mg/kg）的饲料。HLI后，后肢外观，功能和多普勒血流灌注进行了连续评价。腓肠肌肌纤维大小和微血管密度也进行了评估后21天HLI。我们观察到，与接受常规饮食的db/db小鼠和接受卡格列净饮食的+/+小鼠相比，接受含卡格列净饮食的db/db具有显著更差的后肢功能和外观评分。在HLI后第21天，与接受卡格列净饲料的+/+小鼠相比，接受卡格列净饲料的db/db小鼠的多普勒灌注、腓肠肌肌纤维尺寸和微血管密度也降低。这些结果表明，卡格列净似乎阻碍缺血性外周组织恢复，需要在糖尿病和外周动脉疾病史患者中进行进一步临床研究。
There is a reported increased incidence of lower extremity amputations in individuals with diabetes who are treated with canagliflozin (an SGLT2 receptor inhibitor). It is unclear whether this is an unintended consequence of therapy, or whether canagliflozin can affect peripheral limb perfusion in the setting of underling arterial malperfusion. To evaluate this we explored the effect of canagliflozin on tissue recovery following unilateral hind-limb ischemia (HLI). Adult wildtype (+/+) and diabetic (db/db) mice were maintained on 8 weeks of a regular chow diet, or a chow diet containing canagliflozin (200mg/kg). Following HLI, hind-limb appearance, function, and Doppler perfusion were serially evaluated. Gastrocnemius muscle fiber size and microvessel density were also evaluated 21 days following HLI. We observed that db/db that received a canagliflozin containing diet had significantly worse hind-limb function and appearance scores compared to both db/db mice that received a regular diet and +/+ mice that received canagliflozin diet. At post-HLI day 21, db/db mice that received a canagliflozin diet also had decreased Doppler perfusion, gastrocnemius muscle fiber size, and microvessel density compared to +/+ mice that received a canagliflozin diet. These findings indicate that canagliflozin appears to impede ischemic peripheral tissue recovery, and warrant further clinical investigation in individuals with diabetes and a history of peripheral artery disease.