钠-葡萄糖协同转运体2抑制剂坎格列净的研究进展

目的:了解钠-葡萄糖协同转运体2抑制剂坎格列净的药动学、药效学和药物联用研究进展,以期为临床治疗2型糖尿病提供参考。方法:查阅近年来国内外相关文献,对坎格列净的药动学、药效学和药物联用的情况进行归纳和总结。结果与结论:坎格列净对2型糖尿病患者的疗效主要通过其对肾糖阈、尿糖排泄、血糖水平、体质量和胰岛素抵抗的影响实现。2型糖尿病患者给予坎格列净单药治疗后,其糖化血红蛋白、空腹血糖、餐后2 h血糖水平和体质量等方面均明显降低;坎格列净联用二甲双胍、胰岛素,或者与二甲双胍和磺脲类药物三药联用均显示出协同增效作用。坎格列净主要的不良反应为高钾血症和生殖道霉菌感染,但发生率较低,安全性较高。坎格列净为2型糖尿病的治疗提供了新的思路和选择。     

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.     

治疗2型糖尿病的新药坎格列净

目的:介绍2型糖尿病治疗药物坎格列净的研究进展。方法:对坎格列净的作用机制、药效学、药动学、临床疗效及安全性等进行综述。结果与结论:坎格列净是钠-葡萄糖协同转运蛋白2抑制剂,2013年3月29日作为新型的降糖药获美国食品药品管理局批准上市,用于治疗2型糖尿病。临床研究表明,坎格列净作为单药治疗或与二甲双胍、磺脲类药物联合治疗,能有效降低血糖和减轻体质量,不良事件总体发生率与安慰剂相似,但生殖道霉菌感染和渗透性利尿相关的不良事件发生率较安慰剂高,低血糖发生率较低。     

不同剂量坎格列净、西格列汀对2型糖尿病患者疗效及安全性分析:一项网状meta分析研究

目的通过网状meta分析,比较坎格列净和西格列汀对2型糖尿病患者血糖影响的差异。方法检索中国知网、万方数据库、Pubmed、Embase数据库,收集坎格列净、西格列汀相关的临床试验文献,对收集的文献进行质量评价,使用STATA 14软件对提取的数据进行网状meta分析。结果最终共纳入22篇文献,共22项RCT研究,总病例数为11 560例。坎格列净300 mg降低Hb A1c及FPG水平的效果最佳。不良反应事件发生率西格列汀低于坎格列净。结论与西格列汀相比,坎格列净能够明显改善2型糖尿病患者的血糖控制水平,且不良反应较低。     

2017年5月美国FDA公布的药品安全信息

坎格列净(Invokana,Invokamet):药品安全通讯——增加腿和足部的截肢风险 事件: 基于两项大型临床研究的新数据,FDA认为2型糖尿病治疗药坎格列净(Invokana,Invokamet,Invokamet XR) 会增加腿和足的截肢风险. FDA要求在坎格列净的标签中加入上述新增风险的警示, 包括最严厉的黑框警告.     

SGLT2抑制剂托格列净的研究进展

托格列净(Tofogliflozin)是一种口服活性小分子SGLT2抑制剂,由日本中外(Chugai)制药开发并用于2型糖尿病(T2DM)的治疗.托格列净对SGLT2的选择性抑制作用是SGLT1的2900多倍,与达格列净、坎格列净、伊格列净、伊帕列净和鲁格列净相比具有更强的选择性.本文对托格列净的发现、药效学、药代动力学、副作用及合成路线进行综述.     

达格列净的药理及临床研究概述

本文综述了达格列净在治疗2型糖尿病的药效学、药动学、临床研究及安全性。达格列净作为钠-葡萄糖协同转运蛋白2抑制药,能够降低HbA1c、空腹血糖及体质量,耐受性较好;主要且较严重的不良反应为生殖系统感染;目前尚有降压作用仍在研究中。     

达格列净和沙格列汀复方制剂治疗2型糖尿病研究进展

摘 要沙格列汀是一种二肽基肽酶-4(DPP-4)抑制药,达格列净为钠 葡萄糖协同转运蛋白2（SGLT2）抑制药。两药复方制剂已被美国FDA批准用于成人2型糖尿病的治疗。达格列净有增加内源性葡萄糖的作用,沙格列汀降低内源性葡萄糖的作用,两药在体内没有相互作用。短期和长期的临床试验证明,两药联合应用能够很好地控制患者的血糖,低血糖的发生率很低,也不增加患者的体重。     

已上市钠-葡萄糖协同转运蛋白2抑制剂临床药动学特点比较

钠-葡萄糖协同转运蛋白2(sodium-glucose cotransporter type 2,SGLT2)参与肾脏对90%葡萄糖滤过液的重吸收,在血糖调节中发挥重要作用。SGLT2抑制剂作为2型糖尿病治疗的新靶点,受到广泛关注。目前,已有卡格列净、达格列净、依帕列净、依格列净、托格列净、鲁格列净6种SGLT2抑制剂在美国和日本上市,本研究对已上市的SGLT2抑制剂临床药动学特点进行了比较和综述。     

钠-葡萄糖共转运体2抑制剂鲁格列净

鲁格列净为高选择性钠-葡萄糖共转运体2抑制剂,通过阻止肾脏对葡萄糖的重吸收,增加葡萄糖在尿中的排泄,降低血糖水平。主要用于成人2型糖尿病的治疗,无论是单独应用,还是与其他降血糖药物合用,均能有效地降低患者糖化血红蛋白水平。鲁格列净不良反应轻微,患者具有较好的耐受性。     

Canagliflozin:治疗2型糖尿病的新型钠-葡萄糖共转运体2抑制剂

钠-葡萄糖共转运体2(SGLT2)是近年来新发现的2型糖尿病治疗靶点。抑制SGLT2可减少肾脏葡萄糖的重吸收,增加尿糖排出,从而降低血糖。Canagliflozin是SGLT2抑制剂,可结合饮食控制和运动来改善成人2型糖尿病的血糖。Canagliflozin的推荐剂量为100 mg,口服,每日1次。临床试验表明canagliflozin治疗2型糖尿病安全有效,耐受性好。     

Renal effects of canagliflozin in type 2 diabetes mellitus

Background:

Chronic kidney disease is commonly associated with type 2 diabetes mellitus (T2DM) and may impact the efficacy and safety of glucose-lowering therapies. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces blood glucose levels in patients with T2DM by lowering the renal threshold for glucose, thereby promoting urinary glucose excretion. This review describes the pharmacology, efficacy and safety of canagliflozin according to kidney function in participants with T2DM.

Methods:

Published articles that reported efficacy, safety and pharmacokinetics/pharmacodynamics data for canagliflozin in patients with T2DM and impaired renal function, and renal safety data with canagliflozin in various populations of patients with T2DM through May 2015 were included.

Results:

Early transient reductions in estimated glomerular filtration rate were observed with canagliflozin; these changes generally stabilized or attenuated over time and reversed after discontinuation, suggesting no renal (glomerular or tubular) damage with canagliflozin treatment. Urinary albumin-to-creatinine ratios were reduced with canagliflozin. Canagliflozin was generally well tolerated in patients with normal or mild to moderately impaired renal function, with a modestly higher incidence of renal-related adverse events and volume depletion–related adverse events in patients with moderate renal impairment. Adverse events related to potassium elevations were infrequent with canagliflozin 100?mg regardless of kidney function status; however, patients with moderately impaired kidney function experienced hyperkalemia more frequently with canagliflozin 300?mg compared with patients treated with either canagliflozin 100?mg or placebo. Canagliflozin was not associated with increased cardiovascular risk across studies; however, relatively few events among patients with impaired renal function meant that the analysis was not adequately powered to examine this outcome, and results from separate trials are awaited.

Conclusions:

Overall, canagliflozin is associated with small, transient changes in kidney function, and is well tolerated in patients with T2DM with varying kidney function status.     

Efficacy and safety of canagliflozin in type 2 diabetes mellitus: systematic review of randomized controlled trials

Background: Currently available antihyperglycemic agents (AHAs), despite being effective, do not provide adequate glycemic control in some cases and are associated with side effects. A sodium glucose co-transporter 2 inhibitor, canagliflozin, is a newer AHA, which acts by decreasing the reabsorption of filtered glucose thereby elevating the urinary glucose excretion in diabetics.

Areas covered: This systematic review was completed to assess the clinical effectiveness and safety of canagliflozin in T2DM. A literature search in PubMed, MEDLINE, Cochrane and ClinicalTrials.gov was conducted for randomized clinical trials of canagliflozin as an AHA by applying predetermined inclusion and exclusion criteria. Total 13 studies were included in the systematic review. The main outcomes assessed were change in HbA1c and fasting plasma glucose.

Expert opinion: Canagliflozin monotherapy or combination therapy has the potential to decrease inadequately controlled hyperglycemia in T2DM. It acts by a novel insulin independent mechanism which complements the action of the existing AHA and improves glycemic control and decreases the body weight. Safety profile of canagliflozin indicates lower number of hypoglycemic episodes. Some manageable adverse events include genital mycotic infections, urinary tract infections, osmotic diuresis-related events etc. These findings affirm the utility of canagliflozin in T2DM; however, data on long-term safety and efficacy are needed.     

Canagliflozin – something new for type 2 diabetes,but is it safe and efficacious?

Introduction: Inhibition of the sodium-glucose cotransporter 2 (SGLT2), to promote the excretion of glucose, is a new paradigm in the treatment of type 2 diabetes.

Areas covered: Canagliflozin is an SGLT2 inhibitor, which has been the subject of two recent clinical trials, which are evaluated.

Expert opinion: Studies with canagliflozin, in subjects with type 2 diabetes, have shown that its use is associated with reductions in HbA1c and body weight and small reductions in blood pressure and triglycerides, while increasing high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. As monotherapy in Japanese subjects, or in comparison with glimepiride in CANTATA-SU (CANagliflozin Treatment and Trial Analysis versus SUlphonylurea), canagliflozin causes a low incidence of hypoglycemia, and this is an advantage over glimepiride. However, one of the disadvantages with canagliflozin, which was also highlighted in CANTATA-SU, is that canagliflozin can cause urogenital infections, which are not observed with other antidiabetic drugs. The Federal Drug Administration has recently approved canagliflozin for use in type 2 diabetes, while directing that a clinical outcome safety trial be undertaken. We are concerned that canagliflozin has been approved for use in type 2 diabetes prior to a clinical outcome study of efficacy being undertaken and without the outcome of further safety testing.     

A safety evaluation of canagliflozin: a first-in-class treatment for type 2 diabetes

Introduction: Numerous treatments are available for type 2 diabetes mellitus (T2DM), which can improve insulin sensitivity or stimulate its secretion. These are usually unable to halt progression. Inhibition of glucose reabsorption from the renal filtrate was proposed as a novel therapeutic target. Sodium/glucose co-transporter 2 (SGLT2) inhibitors were developed accordingly, with canagliflozin the first to launch in the US in 2013.

Areas covered: The mechanism of action of canagliflozin, its pharmacokinetic data and its clinical applications and efficacy data from clinical studies of both subjects with T2DM controlled on diet and exercise, and those on glucose-lowering agents and insulin. The evaluation focuses primarily on the safety of canagliflozin in clinical trials conducted for initial registration due to limited post-marketing data, discusses safety in special populations, before comparing its safety with existing therapies.

Expert opinion: Canagliflozin offers a novel therapeutic approach to T2DM; advantages include weight loss and blood pressure lowering with a low intrinsic risk of hypoglycaemia. The main adverse effects likely to be seen are a very small increase in risk of urinary tract infections and a modest risk of developing genital fungal infections. Studies suggest no increased risk of cardiovascular (CV) disease, but longer duration outcome studies are essential.     

The effects of canagliflozin,a sodium glucose co-transporter 2 inhibitor,on mineral metabolism and bone in patients with type 2 diabetes mellitus

Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors lower blood glucose levels in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. This review provides a comprehensive summary of preclinical and clinical data on the effects of the SGLT2 inhibitor canagliflozin on mineral balance and bone.

Methods: Published articles and internal study reports through November 2015 were included.

Results: In clinical studies, canagliflozin was not associated with meaningful changes in serum or urine calcium, parathyroid hormone, or vitamin D. Canagliflozin was associated with increases in serum magnesium and phosphate without changes in their urinary excretion. Increases in serum collagen type-1 beta-carboxy-telopeptide (beta-CTX), a bone resorption marker, and osteocalcin, a bone formation marker, were observed with canagliflozin. Decreases in total hip bone mineral density (BMD) of up to 1.2% were seen with canagliflozin after 2 years; no changes in BMD were seen at other skeletal sites. Changes in total hip BMD and serum beta-CTX with canagliflozin correlated with decreases in body weight. In a clinical program-wide analysis, canagliflozin was associated with increased fracture risk that was driven by a higher incidence in the cardiovascular safety study (CANVAS), with no fracture imbalance seen in pooled data from other Phase 3 studies. The fracture imbalance occurred within 12 weeks after initiating treatment, most frequently in the distal portion of the upper and lower extremities.

Conclusions: Across clinical studies, canagliflozin did not meaningfully affect calcium homeostasis or hormones regulating calcium homeostasis. Increases in bone turnover markers and decreases in BMD at the total hip, but not at other sites, that correlated with weight loss were seen with canagliflozin. Canagliflozin was associated with a higher fracture incidence within 12 weeks, primarily in distal extremities. Data from ongoing canagliflozin studies will provide additional information on fracture risk.     

Physiologically based pharmacokinetic–pharmacodynamic modeling to predict concentrations and actions of sodium‐dependent glucose transporter 2 inhibitor canagliflozin in human intestines and renal tubules

Canagliflozin is a recently developed sodium‐glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic–pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized. Therefore, a physiologically based pharmacokinetic (PBPK) model of canagliflozin was developed based on clinical data from healthy volunteers and it was used to simulate luminal concentrations in intestines and renal tubules. In small intestine simulations, the inhibition ratios for SGLT1 were predicted to be 40%–60% after the oral administration of clinical doses (100–300 mg/day). In contrast, inhibition ratios of canagliflozin for renal SGLT2 and SGLT1 were predicted to be approximately 100% and 0.2%–0.4%, respectively. These analyses suggest that canagliflozin only inhibits SGLT2 in the kidney. Using the simulated proximal tubule luminal concentrations of canagliflozin, the urinary glucose excretion rates in canagliflozin‐treated diabetic patients were accurately predicted using the renal glucose reabsorption model as a PD model. Because the simulation of canagliflozin pharmacokinetics was successful, this PBPK methodology was further validated by successfully simulating the pharmacokinetics of dapagliflozin, another SGLT2 inhibitor. The present results suggest the utility of this PBPK/PD model for predicting canagliflozin concentrations at target sites and help to elucidate the pharmacological effects of SGLT1/2 inhibition in humans. Copyright © 2016 John Wiley & Sons, Ltd.     

Syntheses of isotope‐labeled SGLT2 inhibitor canagliflozin (JNJ‐28431754)

Canagliflozin (Invokana, JNJ‐28431754) is an orally bioavailable and selective SGLT2 (subtype 2 sodium‐glucose transport protein) inhibitor approved for the treatment of type 2 diabetes. Herein, we report the synthesis of ¹³C and ¹⁴C‐labeled canagliflozin. Stable isotope‐labeled [¹³C₆]canagliflozin was synthesized in 4 steps starting from [¹³C₆]‐labeled glucose. The [¹⁴C]‐Labeled canagliflozin was synthesized by incorporation of [¹⁴C] into the benzylic position between the thiophene and benzene rings of the compound. Detailed synthesis of the isotope‐labeled compounds is reported.     

Longer-term safety and tolerability of canagliflozin in patients with type 2 diabetes: a pooled analysis

Objective: To evaluate the longer-term safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM).

Methods: The safety/tolerability of canagliflozin 100 and 300?mg were assessed using data pooled from seven placebo- and active-controlled studies of 52–104 weeks in duration that enrolled a broad range of patients with T2DM (N?=?5598). Canagliflozin 100 and 300?mg as monotherapy or in combination with various background antihyperglycemic agents (AHAs) were compared with pooled non-canagliflozin treatments (i.e. placebo, sitagliptin, glimepiride). Safety was assessed based on adverse event (AE) reports, including the incidence of AEs related to the mechanism of SGLT2 inhibition.

Results: Overall AE incidence was similar with canagliflozin 100 and 300?mg and non-canagliflozin (73.7%, 74.5%, and 73.7%). The incidence of AE-related discontinuations and serious AEs was low and balanced across groups. The incidence of male and female genital mycotic infections, urinary tract infections, and AEs related to osmotic diuresis or volume depletion was higher with canagliflozin versus non-canagliflozin; these AEs generally occurred early with decreased incidence over time and incidence was similar across baseline HbA1c subgroups. The incidence of fractures and diabetic ketoacidosis was low and similar across groups. Canagliflozin was associated with a low incidence of hypoglycemia when used with background AHAs that are not associated with hypoglycemia; the incidence was higher among patients on background AHAs associated with hypoglycemia (i.e. insulin, sulfonylurea, glinide).

Limitations: Limitations of this analysis include its post hoc nature. While this analysis included a broad population of patients, including those with a history or risk of cardiovascular disease or chronic kidney disease, the longer-term safety in these patient populations was not specifically evaluated. Ongoing outcome studies will provide data on the long-term safety of canagliflozin in these populations.

Conclusions: Longer-term exposure to canagliflozin as monotherapy or in combination with other agents was generally well tolerated in patients with T2DM.

Trial registration: ClinicalTrials.gov identifiers: NCT01106625, NCT01081834, NCT01106677, NCT00968812, NCT01106651, NCT01106690, NCT01137812.