Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St Louis, MO, USA.
Department of Medicine, Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St Louis, MO, USA.
Vasc Med. 2021 Apr;26(2):131-138. doi: 10.1177/1358863X20961153. Epub 2020 Oct 23.
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 (200 mg/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 diet containing canagliflozin had significantly worse hind-limb function and appearance scores compared to both db/db mice that received a regular diet and +/+ mice that received a 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.
有报道称，在接受卡格列净（一种 SGLT2 受体抑制剂）治疗的糖尿病患者中，下肢截肢的发病率增加。目前尚不清楚这是治疗的意外后果，还是卡格列净是否会影响潜在动脉功能不全情况下的外周肢体灌注。为了评估这一点，我们研究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）小鼠分别维持 8 周的普通饲料饮食或含卡格列净的饲料（200mg/kg）。HLI 后，连续评估后肢外观、功能和多普勒灌注情况。HLI 后 21 天还评估了比目鱼肌纤维大小和微血管密度。我们观察到，接受含卡格列净饮食的 db/db 小鼠的后肢功能和外观评分明显低于接受普通饮食的 db/db 小鼠和接受卡格列净饮食的+/+小鼠。在 HLI 后第 21 天，接受卡格列净饮食的 db/db 小鼠的多普勒灌注、比目鱼肌纤维大小和微血管密度也低于接受卡格列净饮食的+/+小鼠。这些发现表明，卡格列净似乎会阻碍缺血性周围组织的恢复，需要对有糖尿病和外周动脉疾病病史的个体进行进一步的临床研究。
