Sodium glucose co-transporter inhibitors for the management of diabetes mellitus: an opinion paper from the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy

Type 2 diabetes mellitus (T2DM) carries a high prevalence in the United States and worldwide. Therefore, the number of medication classes being developed and studied has grown. The individualized management of diabetes is accomplished by evaluating a medication’s efficacy, safety, and cost, along with the patient’s preference and tolerance to the medication. Sodium glucose co-transporter 2 inhibitors are a new therapeutic class indicated for the treatment of diabetes and have a unique mechanism of action, independent of beta-cell function. The first agent approved by the Food and Drug Administration (FDA) was canagliflozin in March 2013. Two agents – dapagliflozin and empagliflozin – were FDA-approved in January and July 2014, respectively. A clear understanding of the new class is needed to identify its appropriate use in clinical practice. Members of the American College of Clinical Pharmacy Endocrine and Metabolism Practice and Research Network reviewed available literature regarding this therapeutic class. The article addresses the advantages, disadvantages, emerging role, and patient education for sodium glucose co-transporter 2 inhibitors. Key limitations for this article include limited access to clinical trial data not published by the pharmaceutical company and limited data on products produced outside the United States.     

Canagliflozin Prevents Diabetes-Induced Vascular Dysfunction in ApoE-Deficient Mice

Aim: Recent studies have demonstrated that selective sodium–glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular events, although their mechanism remains obscure. We examined the effect of canagliflozin, an SGLT2i, on atherogenesis and investigated its underlying mechanism.Method: Canagliflozin (30 mg/kg/day) was administered by gavage to streptozotocin-induced diabetic apolipoprotein E-deficient (ApoE^−/−) mice. Sudan IV staining was performed at the aortic arch. Immunostaining, quantitative RT-PCR, and vascular reactivity assay were performed using the aorta. In vitro experiments using human umbilical vein endothelial cells (HUVECs) were also performed.Result: Canagliflozin decreased blood glucose (P < 0.001) and total cholesterol (P < 0.05) levels. Sudan IV staining showed that 12-week canagliflozin treatment decreased atherosclerotic lesions (P < 0.05). Further, 8-week canagliflozin treatment ameliorated endothelial dysfunction, as determined by acetylcholine-induced vasodilation (P < 0.05), and significantly reduced the expressions of inflammatory molecules such as ICAM-1 and VCAM-1 in the aorta at the RNA and protein levels. Canagliflozin also reduced the expressions of NADPH oxidase subunits such as NOX2 and p22phox in the aorta and reduced urinary excretion of 8-OHdG, suggesting a reduction in oxidative stress. Methylglyoxal, a precursor of advanced glycation end products, increased the expressions of ICAM-1 and p22phox in HUVECs (P < 0.05, both). Methylglyoxal also decreased the phosphorylation of eNOS^Ser1177 and Akt but increased the phosphorylation of eNOS^Thr495 and p38 MAPK in HUVECs.Conclusion: Canagliflozin prevents endothelial dysfunction and atherogenesis in diabetic ApoE^−/− mice. Anti-inflammatory and antioxidative potential due to reduced glucose toxicity to endothelial cells might be its underlying mechanisms.     

钠-葡萄糖共转运蛋白-2抑制剂的药理学与临床评价

目的：探讨钠-葡萄糖共转运蛋白-2（SGLT-2）抑制剂的药理学作用与临床应用。方法：采用文献分析方法,对国内外SGLT-2抑制剂相关文献进行检索,评价SGLT-2抑制剂的临床疗效与安全性。结果与结论：SGLT-2抑制剂为一类新型抗糖尿病药,临床上用于饮食和运动控制治疗后效果不佳的2型糖尿病者。SGLT-2抑制剂的作用机制与口服降糖药截然不同,其非在于促进胰岛β细胞分泌胰岛素,作用不依赖胰岛素,可延缓糖尿病的进程,发生低血糖的风险小,具有良好的应用前景,但其安全性、经济性、临床获益有待更长期的临床研究来证明。     

2型糖尿病治疗新药坎格列净的研究进展

坎格列净是一种钠-葡萄糖共转运蛋白2抑制药,抑制葡萄糖的肾重吸收,增加葡萄糖的尿排泄.美国FDA于2013年3月批准其上市,用于治疗2型糖尿病.坎格列净可有效降低2型糖尿病患者的血糖水平,还可降低患者体质量和收缩压,且低血糖风险较小.不良反应是增加泌尿生殖道感染.本文就其作用机制、药动学、临床疗效及安全性等作一综述.     

A series of diabetic ketoacidosis associated with the use of sodium-glucose co-transporter-2 inhibitors in secondary care

Background and aimsSodium-glucose co-transporter-2 inhibitors (SGLT-2i) are associated with diabetic ketoacidosis (DKA), however limited case series are published.MethodsWe evaluated the characteristics of patients admitted with SGLT-2i associated DKA.ResultsOver 4 months, 22 patients were identified; 45.5% of DKA was not associated with concurrent illness.ConclusionDKA is not uncommonly associated with SGLT2i with no clear patient factors associated with severity.     

Canagliflozin,an inhibitor of sodium-glucose co-transporter 2, advances in the treatment of type 2 diabetes

Canagliflozin (CANA) is a sodium-glucose co-transporter 2 inhibitor. One of the important mechanisms of CANA is the inhibitory effect on the glucose uptake in the proximal tubule of the nephron, and the other mechanism can be the reduction of inflammatory cytokine expression monocytes and macrophages. It is proved by FDA for the management of type 2 diabetes. In the present work, we summarized the publication and clinical evidence of the CANA on healthy individuals and those with related metabolic diseases, such as type 1 and 2 diabetes, obesity, or cardiovascular and kidney diseases. This drug has been reported to offer potential advantages in regulating body weight and reducing heart failure, hypoglycemia, and stroke risk in patients with type 2 diabetes. Some in vitro and animal experiments also show that this drug has good effects on cancer treatment. However, some case reports and experiments also show the side effect of CANA, such as amputation, fracture, and pancreatitis, while the mechanism is still unknown. Overall, CANA has a good effect on the management of type 2 diabetes by reducing the risk of kidney failure, cardiovascular diseases, and stroke. However, as a new drug, more clinical trials and experiments of CANA should be carried out in the future.     

Update review of the safety of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with type 2 diabetes mellitus

ABSTRACT

Introduction: The safety profile of sodium-glucose cotransporter 2 (SGLT2) inhibitors has continued to evolve with the availability of data from clinical trial programs, post-marketing pharmacovigilance and dedicated cardiovascular outcome trials.

Areas covered: This article reviews the safety issues associated with the SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, particularly the newer/emergent safety data related to US Food and Drug Administration statements regarding these three agents.

Expert opinion: The safety profile of SGLT2 inhibitors is well defined, and the adverse event profile is largely consistent with their mechanism of action. These well-recognized events include genital mycotic infections and volume-associated adverse events. Serious safety issues detected more recently with SGLT2 inhibitor therapy, such as bone fractures, pyelonephritis, urosepsis, and ketoacidosis, have been uncommon. A robust improvement in cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) was recently demonstrated with empagliflozin. Given the glucose-lowering efficacy, low risk of hypoglycemia, and other benefits associated with SGLT2 inhibitor therapy, this class of oral glucose-lowering medication is a valuable addition to treatment options for T2DM, and may play an increasingly prominent therapeutic role as emerging data are revealed.     

Sodium–glucose cotransporter 2 inhibitors: an evidence-based practice approach to their use in the natural history of type 2 diabetes

Objective The sodium–glucose cotransporter 2 (SGLT-2) inhibitors are an important addition to available treatments for patients with type 2 diabetes (T2D) as an adjunct to modifications in diet and exercise. SGLT-2 inhibitors may be prescribed alone or as add-on treatment in patients receiving metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, and/or insulin across the natural history of the disease. Inhibition of SGLT-2, which is responsible for approximately 90% of renal glucose reabsorption, increases urinary glucose excretion and lowers blood glucose concentrations. The objective of this review is to discuss the pathophysiology of diabetes and the contribution of the kidney to glucose homeostasis and to provide an evidence-based practice approach to clinical applications of SGLT-2 inhibitors in the treatment of T2D.

Methods PubMed and Google Scholar databases were searched to identify literature published from 1990 through September 2015 examining the pathophysiology of T2D, the role of the kidney in regulating glucose concentrations, and clinical evidence for the efficacy and safety of SGLT-2 inhibitors in T2D.

Results There is a need for early treatment in patients with T2D to minimize the risk of cardiovascular complications that increase morbidity and mortality. SGLT-2 inhibitors improve glycemic control, reduce body weight and blood pressure, and are associated with a low risk of hypoglycemia. Adverse events associated with SGLT-2 inhibitors include mild to moderate urinary tract and genital infections and mild dehydration potentially leading to orthostatic hypotension.

Conclusions An evidence-based practice approach to examining the importance of early, proactive treatment of T2D using SGLT-2 inhibitors from initiation of pharmacotherapy to increasingly more complicated combination therapy regimens, including insulin, suggests that this treatment strategy maximizes benefits and minimizes potential side effects. The SGLT-2 inhibitors augment the arsenal of available antidiabetes agents, facilitating the ability of clinicians to design tailored treatment regimens that help patients achieve therapeutic goals.