Sodium-glucose cotransporter-2 inhibitor-associated euglycemic diabetic ketoacidosis in COVID-19-infected patients: A systematic review of case reports

BACKGROUND Diabetic ketoacidosis(DKA)manifests as hyperglycemia,metabolic acidosis,and ketosis.However,euglycemic DKA(eu-DKA)conceals severe DKA with glucose levels below 200 mg/dL.Sodium-glucose cotransporter-2(SGLT2)inhibitors can induce eu-DKA in diabetic patients.Notably,coronavirus disease 2019(COVID-19)-infected individuals with diabetes using SGLT2 inhibitors face an augmented risk of eu-DKA due to the direct toxic impact of the virus on pancreatic islets.This study aims to comprehensively investigate the association between SGLT2 inhibitors and eu-DKA in COVID-19 patients through meticulous case report analysis.Additionally,we endeavor to examine the outcomes and treatment approaches for COVID-19-infected diabetics receiving SGLT2 inhibitors,providing indispensable insights for healthcare professionals managing this specific patient population.AIM To investigate the connection between SGLT2 inhibitors and euglycemic DKA in COVID-19 patients through a meticulous analysis of case reports.METHODS We conducted an exhaustive search across prominent electronic databases,including PubMed,SCOPUS,Web of Science,and Google Scholar.This search encompassed the period from December 2019 to May 2022,incorporating published studies and pre-prints.The search terms employed encompassed“SGLT2 inhibitors”,“euglycemic DKA”,“COVID-19”,and related variations.By incorporating these diverse sources,our objective was to ensure a thorough exploration of the existing literature on this subject,thereby augmenting the validity and robustness of our findings.RESULTS Our search yielded a total of seven case reports and one case series,collectively comprising a cohort of twelve patients.These reports detailed instances of eu-DKA in individuals with COVID-19.Crucially,all twelve patients were utilizing SGLT2 as their primary anti-diabetic medication.Upon admission,all oral medications were promptly discontinued,and the patients were initiated on intravenous insulin therapy to effectively manage the DKA.Encouragingly,eleven patients demonstrated a favorable outcome,while regrettably,one patient succumbed to the condition.Subsequently,SGLT2 were discontinued for all patients upon their discharge from the hospital.These findings provide valuable insights into the clinical management and outcomes of eu-DKA cases associated with COVID-19 and SGLT2,underscoring the critical importance of prompt intervention and vigilant medication adjustments.CONCLUSION Our study sheds light on the possibility of diabetic patients developing both drug-related and unrelated DKA,as well as encountering adverse outcomes in the context of COVID-19,despite maintaining satisfactory glycemic control.The relationship between glycemic control and clinical outcomes in COVID-19 remains ambiguous.Consequently,this systematic review proposes that COVID-19-infected diabetic patients using SGLT2 should contemplate alternative treatment protocols until their recovery from the disease.

Renal glucosuria in children

The kidneys play a critical role in maintaining glucose homeostasis.Under normal renal tubular function,most of the glucose filtered from the glomeruli is re-absorbed in the proximal tubules,leaving only trace amounts in the urine.Glycosuria can occur as a symptom of generalized proximal tubular dysfunction or when the reabsorption threshold is exceeded or the glucose threshold is reduced,as seen in familial renal glycosuria(FRG).FRG is characterized by persistent glycosuria despite normal blood glucose levels and tubular function and is primarily associated with mutations in the sodium/glucose cotransporter 5A2 gene,which encodes the sodium-glucose cotransporter(SGLT)2.Inhibiting SGLTs has been proposed as a novel treatment strategy for diabetes,and since FRG is often considered an asymptomatic and benign condition,it has inspired preclinical and clinical studies using SGLT2 inhibitors in type 2 diabetes.However,patients with FRG may exhibit clinical features such as lower body weight or height,altered systemic blood pressure,diaper dermatitis,amino-aciduria,decreased serum uric acid levels,and hypercalciuria.Further research is needed to fully understand the pathophysiology,molecular genetics,and clinical manifestations of renal glucosuria.

Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice

BACKGROUND Modern guidelines recommend sodium-glucose cotransporter-2(SGLT2)inhibitors as the preferred antihyperglycemic agents for patients with type 2 diabetes and chronic kidney disease.However,the mechanisms underlying the renal protective effect of SGLT2 inhibitors are not fully understood.structure of podocytes and nephrin expression in glomeruli in db/db diabetic mice.METHODS We treated 8-wk-old male db/db mice with EMPA(10 mg/kg/d)or vehicle for 8 wk.Age-matched male db/+mice were included as non-diabetic controls.Parameters of body composition,glycemic and lipid control,and plasma concentrations of leptin,insulin and glucagon were assessed.We evaluated renal hypertrophy as kidney weight adjusted to lean mass,renal function as plasma levels of creatinine,and albuminuria as the urinary albumin-to-creatinine ratio(UACR).Renal structures were studied by light and transmission electron microscopy with a focus on mesangial volume and podocyte structure,respectively.Glomerular nephrin and transforming growth factor beta(TGF-β)were assessed by immunohistochemistry.RESULTS Severe obesity and hyperglycemia developed in db/db mice prior to the start of the experiment;increased plasma concentrations of fructosamine,glycated albumin,cholesterol,leptin,and insulin,and elevated UACR were detected.Mesangial expansion,glomerular basement membrane thickening,and increased area of TGF-βstaining in glomeruli were revealed in vehicle-treated mice.Podocytopathy was manifested by effacement of foot processes;nephrin-positive areas in glomeruli were reduced.EMPA decreased the levels of glucose,fructosamine and glycated albumin,UACR,kidney hypertrophy,mesangial expansion,glomerular basement membrane thickening,and glomerular TGF-βstaining,alleviated podocytopathy and restored glomerular staining of nephrin.CONCLUSION These data indicate that EMPA attenuates podocytopathy in experimental diabetic kidney disease.The anti-albuminuric effect of EMPA could be attributed to mitigation of podocyte injury and enhancement of nephrin expression.

恒格列净致急性肾衰竭

1例45岁男性2型糖尿病患者因血糖控制不佳、高血压病、高脂血症等在门冬胰岛素30和阿卡波糖治疗的基础上加用恒格列净(10 mg、1次/d)、依那普利、非诺贝特、非奈利酮、塞来昔布、乙哌立松和甲钴胺。加用药物前,患者血清肌酐(Scr)和血尿素氮(BUN)无异常。因其他症状相继好转,患者自行停用塞来昔布、非奈利酮和非诺贝特。用药第36天,患者腰部出现阵发性疼痛,逐渐加重,2 d后患者自行停用恒格列净(其余药物不变),次日实验室检查示Scr 180μmol/L、BUN 9.6 mmol/L,诊断为急性肾衰竭。给予止痛、解痉、激素冲击治疗,患者腰部疼痛逐渐好转。停用恒格列净第6天,Scr 142μmol/L、BUN 9.4 mmol/L;停药第9天,Scr 113μmol/L、BUN 9.1 mmol/L;停药约3个月后,Scr 66μmol/L、BUN 6.0 mmol/L。