br Sodium glucose co transporter inhibitors

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are the latest class of non-insulin glucose-lowering agents that facilitate glycaemic control by inhibiting renal glucose reabsorption, thus promoting glycosuria. Canagliflozin, dapagliflozin, and empagliflozin are the three commonly used agents worldwide. Their unique mode of action is independent of beta-cell function. In addition to glycaemic effects, their extra-glycaemic cardiovascular benefits include weight loss, reduction in blood pressure, and a decrease in cardiovascular deaths. They are recommended for use as second-line therapy for the treatment of type 2 inhibitor of apoptosis proteins (T2D), or as a first-line agent where metformin is not tolerated especially in patients with T2D and established cardiovascular disease. They can be prescribed in conjunction with insulin and other oral non-insulin glucose-lowering agents, with multiple oral combination formulations available. These features make SGLT2i a popular choice amongst primary care physicians and specialists for the treatment of T2D. However, because of the rare but serious complication of euglycaemic diabetic ketoacidosis (EDKA), they have become a management issue perioperatively. Sodium-glucose co-transporter-2 inhibitor-associated EDKA is a major adverse event where capillary blood glucose (CBG) concentrations may be within or near the normal range (<14.0 mM L). Whilst classical diabetic ketoacidosis (DKA) occurs most commonly in type 1 diabetes mellitus (T1D), SGLT2i-associated DKA can occur in T2D and can be precipitated by intercurrent illness, surgery, fasting, and reduced carbohydrate intake. The event rate of SGLT2i-associated DKA in a predominant non-operative setting is estimated to be between 1.8 and 4.9 cases per 1000 patient years, ; however, the incidence within perioperative patients remains unknown.
Introduction Statins, such as atorvastatin and simvastatin, have been proved to reduce major cardiovascular events in both primary and secondary prevention via inhibiting cholesterol synthesis [1], [2]. Diabetes mellitus is associated with hypercholesterolemia and hyperlipidemia [3], [4], [5], thus statins are also widely used for type 2 diabetic patients, although these agents may cause some unusual side effects such as rhabdomyolysis, hepatotoxicity, peripheral neuropathy, impaired myocardial contractility and autoimmune diseases [6]. Importantly, clinical studies including large scale randomized controlled trials [7], [8], [9], [10], [11], [12] have demonstrated that long-term treatment of statins may increase the risk of incident diabetes or worsen hyperglycaemia. A clinical report on statin users (N = 53,212) and non-statin users (N = 53,212) showed that statin use was significantly associated with increased risk of incidentdiabetes, which was dependent on individual statins. Atorvastatin, fluvastatin, lovastatin, rosuvastatin and simvastatin but not pravastatin promoted a significant increase in this risk [12]. Moreover, the risk increased by atorvastatin and simvastatin is dose-dependent [11]. In general, homeostatic regulation of blood glucose is involved in multi organs including liver, adipose and skeletal muscle [13]. In liver, glucokinase (GCK) is a critical regulator of glycolysis and glucose transporter 2 (GLUT2) is the main glucose transporter. Their counterparts in adipose and skeletal muscle are hexokinase II (HXKII) and GLUT4, respectively. Statins might elicit detrimental effects on glucose metabolism via inhibiting insulin secretion [14], [15] or insulin-induced glucose uptake in peripheral tissues [13], [16], [17], [18]. We once reported that atorvastatin but not pravastatin impaired glucose utilization partly via repressing hepatic GLUT2 and GCK expressions [16]. Atorvastatin also could reduce GLUT4 protein levels in the adipocytes and decrease uptake of glucose into adipocytes [19]. Similarly, simvastatin might down-regulate expression of GLUT4 protein in 3T3-L1 adipocytes [20]. Skeletal muscle is a primary site of glucose uptake, disposal and storage, accounting for approximately 75% of the entire body’s glucose uptake [21]. These findings indicate that atorvastatin may also impair glucose utilization in skeletal muscle via inhibiting expression and function of GLUT4, contributing to the increased risk of incident diabetes.