An evaluation of empagliflozin and it’s applicability to hypertension as a therapeutic option

ABSTRACT

Introduction

Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as Empagliflozin are novel antihyperglycemic drugs approved for the treatment of type 2 diabetes (T2D). In addition to its glucose-lowering effects, Empagliflozin promotes weight loss, blood pressure reduction, and other beneficial metabolic benefits.     

Review of empagliflozin monotherapy for previously untreated patients with type 2 diabetes mellitus: Comparison with sitagliptin

This Practice Pearl provides a review and brief commentary of the 24-week, double-blind, parallel-group, randomized, Phase III study by Roden et al., which assessed the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin, 10 mg or 25 mg as monotherapy, versus placebo and the dipeptidyl peptidase-4 inhibitor sitagliptin, in previously untreated patients with type 2 diabetes mellitus (T2DM). Compared to placebo, empagliflozin improved glycemic control, with additional benefits on bodyweight and systolic blood pressure, versus placebo and sitagliptin. Treatment was well tolerated. The authors concluded that empagliflozin is a potential new approach to treat patients with T2DM who are inadequately controlled with diet and exercise alone. This paper advances our understanding of empagliflozin, which so far, appears to be a promising therapeutic option for the management of patients with T2DM.     

HPLC法测定恩格列净有关物质的方法学验证

目的：建立恩格列净原料药纯度及所含杂质的测定方法。方法：采用高效液相色谱（HPLC）法,用Waters symmetry C18色谱柱（250 mm×4.6 mm,5 μm）,以0.01%（V/V）三氟乙酸溶液为流动相A,乙腈为流动相B,线性梯度洗脱：0~10 min,流动相B 32%;10~50 min,流动相B 32%~95%;检测波长225 nm,流速1.0 mL/min,柱温45℃。结果：恩格列净与各杂质的分离度均>1.5,检出限均<9 ng/mL, 线性范围满足定量分析要求;重复性试验相对标准差（RSD）均<5%;供试品溶液和对照溶液在8 h内稳定性良好;各杂质的回收率为88.6%~106.1%,RSD均<10%。结论：本研究建立的方法检测灵敏度高,精密度好,可作为恩格列净原料药有关物质的控制方法。     

恩格列净及达格列净对棕榈酸诱导的心肌细胞损伤的保护作用及其机制

目的 探讨钠-葡萄糖共转运蛋白-2抑制剂恩格列净（empagliflozin,EMPA）及达格列净（dapagliflozin,DAPA）对棕榈酸（palmitic acid,PA）诱导H9c2心肌细胞损伤的保护作用及其可能机制。方法 采用PA诱导H9c2心肌细胞损伤,CCK-8法筛选PA、EMPA及DAPA的最佳给药浓度;Western blotting检测TLR4、p-AKT、p-mTOR、Nrf2和HO-1的蛋白表达水平;ELISA法检测IL-1β、IL-6和TNF-α的含量;荧光显微镜和流式细胞术检测PA诱导H9c2心肌细胞中ROS水平。结果 PA 100 μmol·L^–1刺激24 h可诱导H9c2心肌细胞存活率明显下降（P<0.01）,IL-1β、IL-6、TNF-α、TLR4蛋白表达、p-mTOR蛋白表达及ROS水平明显增加（P<0.01）,p-AKT、Nrf2和HO-1蛋白表达显著降低（P<0.01）;与模型组比较,经EMPA及DAPA处理后,细胞存活率明显增加（P<0.01）,IL-1β、IL-6、TNF-α、TLR4蛋白表达、p-mTOR蛋白表达及ROS水平明显降低（P<0.05或P<0.01）,p-AKT、Nrf2和HO-1蛋白表达显著上调（P<0.05或P<0.01）。结论 EMPA及DAPA对PA诱导的心肌细胞损伤均具有保护作用,其机制可能与下调TLR4、p-mTOR蛋白表达,增强AKT蛋白磷酸化,激活Nrf2/HO-1通路,抑制ROS的生成有关。     

Effects of sodium-glucose cotransporter-2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have been shown to mitigate the risks of cardiovascular (CV) and renal complications in patients with type 2 diabetes (T2D) and CV risk factors or CV disease (CVD). In CV outcomes trials (CVOTs) of patients with T2D and established CVD or multiple CV risk factors, empagliflozin and canagliflozin were associated with significant reductions in the risks of major adverse CV events (MACE), hospitalization for heart failure (HF) and kidney disease progression. In the DECLARE–TIMI 58 study, in which the majority of patients did not have established CVD, dapagliflozin was associated with significant reductions in the composite end point of CV death or hospitalization for HF and was noninferior to placebo with regard to MACE; although patients had relatively good renal function, dapagliflozin also showed renal benefits similar to those seen with empagliflozin and canagliflozin. This article reviews the increased risk of CVD and renal disease in patients with T2D and discusses the potential mechanisms of the cardioprotective and renoprotective effects of SGLT-2i therapy. The observed improvements in CV and renal outcomes with SGLT-2is in CVOTs suggest a class effect in this patient population and have influenced treatment guidelines for the way add-on therapy to metformin is initiated in patients with T2D and high CV risk. The overall cardioprotective and renoprotective effects of SGLT-2is in patients with T2D and high CV risk are most likely attributable to multiple mechanisms, including cardiac, haemodynamic, metabolic, anti-inflammatory and renal effects.     

Empagliflozin/linagliptin single-pill combination therapy for patients with type 2 diabetes mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is typically progressive, with sequential addition of therapies often needed to address increasing hyperglycemia over the disease course. Using treatments in combination may be preferred to sequential addition, as a means of providing a more rapid clinical response and potentially avoiding clinical inertia. In such cases, a single-pill combination can help to reduce pill burden. Although various single-pill combinations of oral glucose-lowering agents are available, empagliflozin/linagliptin was the first approved combination of a sodium glucose co-transporter 2 (SGLT2) inhibitor with a dipeptidyl peptidase 4 (DPP-4) inhibitor in the United States.

Areas covered: Two publications of the clinical trial investigating the efficacy and safety of single-pill combinations of empagliflozin/linagliptin in treatment-naive or metformin-treated patients with T2DM (NCT01422876) are reviewed, and their potential impact on clinical practice is discussed.

Expert opinion: The study discussed provides evidence for the efficacy and safety of empagliflozin/linagliptin single pills. Addition of an empagliflozin/linagliptin single pill may be considered in patients with inadequate glycemic control on metformin, or as an alternative to first-line treatment with empagliflozin or linagliptin when metformin is not suitable, particularly in patients with very poor glycemic control, or those who need to achieve target more quickly.     

Sodium-glucose cotransporter-2 inhibitors and genital and urinary tract infections in type 2 diabetes

Coincident with the high and increasing worldwide prevalence of type 2 diabetes (T2D), a growing armamentarium of antidiabetes medications has been introduced to target different organ systems that play a role in the pathophysiology of T2D. Among these, the sodium-glucose cotransporter-2 (SGLT-2) inhibitors were introduced in the United States in 2013 as a new treatment option to address the hyperglycemia associated with T2D. SGLT-2 inhibitors decrease renal glucose reabsorption, resulting in glucosuria, alleviation of hyperglycemia, and modest weight loss and are associated with a low risk of hypoglycemia. The SGLT-2 inhibitors have been linked to an increased incidence of genital mycotic infections and, to a lesser extent, urinary tract infections, which may limit their utility in some patients. This review examines the prevalence, recurrence rates, treatment options, and responses to treatment of genital and urinary tract infections in patients with T2D receiving SGLT-2 inhibitors, with the aim of guiding clinicians in the most effective use of these agents for the treatment of hyperglycemia.     

Empagliflozin for the treatment of type 2 diabetes mellitus: An overview of safety and efficacy based on Phase 3 trials 艾格列净治疗2型糖尿病：基于3期试验的安全性与有效性概述

In the treatment of type 2 diabetes mellitus (T2DM), a relatively new class of oral agents inhibits sodium–glucose cotransporter 2 (SGLT2), reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Numerous SGLT2 inhibitors have been approved for the treatment of T2DM in adults, most recently empagliflozin, which was approved in Europe and the US in 2014. The Phase 3 program has enrolled >14 000 patients and has assessed the efficacy and safety of empagliflozin as monotherapy and in combination. These studies have demonstrated improvements in glycemic control, and modest reductions in body weight and blood pressure. Empagliflozin was generally well tolerated, with no increased risk of hypoglycemia versus placebo as monotherapy or as add‐on therapy, except when given with sulfonylurea. The studies showed an increased risk of urinary tract and genital infections with empagliflozin, although most infections were mild to moderate in intensity. Furthermore, small (but clinically insignificant) increases in hematocrit and lipid levels have been observed for empagliflozin. Due to the mode of action of empagliflozin, care should be exercised when treating patients at risk of volume depletion. The risks and benefits must be weighed for each patient, but the data reviewed herein show promise for empagliflozin as a treatment for patients with T2DM.