Dapagliflozin and saxagliptin tablets for adults with type 2 diabetes

Introduction: Saxagliptin (a dipeptidyl peptidase-4 inhibitor, DPP-4i) and dapagliflozin (a sodium-glucose cotransporter type 2 inhibitor, SGLT2i) improve glucose control in type 2 diabetes (T2D) through different potentially complementary mechanisms, thus offering the opportunity for a combined therapy.

Area covered: The characteristics of the saxagliptin/dapagliflozin combination are analysed, focusing on: 1) pharmacokinetic and pharmacodynamic properties; 2) efficacy and safety in phase III trials with concurrent and sequential add-on therapy; and 3) potential use in clinical practice, including in special populations (cardiovascular disease, heart failure, chronic kidney disease, elderly).

Expert commentary: Conclusions drawn from clinical trials investigating combination with the separate drugs are considered to apply to the fixed-dose combination (FDC) that demonstrates bioequivalence. Dual saxagliptin/dapagliflozin therapy is more potent than either monotherapy and can be used as an initial combination or a stepwise sequential approach. Dual therapy is generally well tolerated and may be used in special populations, with some limitations because of the presence of dapagliflozin. However, the latter may offer some advantages because of multiple effects attributed to SGLT2i. The best place of this dual combination for the management of T2D and the profile of patients who will make the most of this combined therapy remains to be defined.     

SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment

Introduction: Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) offer a new opportunity for the management of type 2 diabetes mellitus. These agents reduce hyperglycemia by decreasing the renal glucose threshold and thereby increasing urinary glucose excretion. Subsequent reduction of glucotoxicity improves beta-cell sensitivity to glucose and tissue insulin sensitivity.

Areas covered: This article analyzes the efficacy and safety data of canagliflozin, dapagliflozin and empagliflozin in randomized controlled trials of 24 – 104 weeks duration, compared with placebo or an active comparator, in patients treated with diet/exercise, metformin, dual oral therapy or insulin.

Expert opinion: SGLT2 inhibitors significantly and consistently reduce glycated hemoglobin, with a minimal risk of hypoglycemia. The improvement of glucose control is similar or slightly better compared with metformin, sulfonylureas or sitagliptin, with the add-on value of significant reductions in body weight and blood pressure. However, caution is recommended in fragile elderly patients and patients with chronic kidney disease. An increased risk of genital mycotic infections is observed, but urinary tract infections are rare. Concern about an unexpected risk of euglycemic ketoacidosis has been recently reported. A possible renal protection deserves further attention. A remarkable reduction in cardiovascular mortality was reported in EMPA-REG OUTCOME with empagliflozin.     

Dapagliflozin for the treatment of type 1 diabetes mellitus

Introduction: In 2017, the management of type 1 diabetes mellitus (T1DM) remains intriguing for the clinician, who has to balance between adequate glycemic control and untoward events related to insulin up-titration. Thus, agents that will complement insulin actions and reduce adverse effects are highly welcome.

Areas covered: In this review, the authors summarize results from studies on the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin in T1DM.

Expert opinion: In T1DM, dapagliflozin is associated with significant antihyperglycemic and metabolic properties, which are achieved with reduction or stabilization of insulin dose and with a very low trend for hypoglycemia. However, there is a lot to learn with respect to diabetic ketoacidosis (DKA), bone fractures and lower limb ischemia.     

Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus

Introduction: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a novel class of agents for the treatment of type 2 diabetes mellitus (T2DM). By inhibiting SGLT2, they prevent renal glucose reabsorption, resulting in glucosuria.

Areas covered: The rationale for development of SGLT2 inhibitors is reviewed, with particular focus on the nine SGLT2 inhibitors currently in development. The authors compare the potency and SGLT2 selectivity of the agents, as well as the results from both animal and clinical studies, considering the potential implications they may have for clinical use.

Expert opinion: Current evidence suggests that SGLT2 inhibitors have similar efficacy in terms of glycemic control and also demonstrate benefits beyond glycemic reductions, including reductions in body weight and modest reductions in blood pressure. Additionally, they appear to preserve beta-cell function and improve insulin sensitivity. Their mechanism of action allows for combination of SGLT2 inhibitors with other antidiabetic drugs and use across the treatment continuum for T2DM. Potential differences in safety and efficacy based on observed differences in potency and selectivity among the SGLT2 inhibitors, particularly versus SGLT1, remain to be seen. Further long-term data, including post-marketing surveillance, are required to fully determine the safety profile of SGLT2 inhibitors in large patient groups.     

Dapagliflozin therapy in type-2 diabetes: current knowledge and future perspectives

Dapagliflozin is a new antidiabetic agent that belongs to the class of sodium glucose transporter 2 (SGLT-2) inhibitors. By decreasing renal glucose absorption, these agents target hyperglycemia independent of insulin secretion or insulin sensitivity. This unique mechanism of action differentiates them from existing antidiabetic agents currently on the market. It has been hypothesized that SGLT-2 inhibitors can be effectively and safely combined with other agents, including insulin, and incretin-based therapies. They can be used either as monotherapy, or in dual- or triple-agent combinations. Dapagliflozin has been shown to be effective and safe in patients with type-2 diabetes, with modest but significant reductions in HbA1c and a number of potentially beneficial and sustained non-glycemic effects, including those on body weight, plasma lipids and systolic blood pressure. In addition, dapagliflozin has been shown to have a generally favorable safety profile and is well tolerated. Ongoing studies may provide definitive answers on the cardiovascular safety and efficacy of SGLT-2 inhibitors in patients with type-2 diabetes.     

Dapagliflozin: a review on efficacy,clinical effectiveness and safety

Introduction: The prevalence of type 2 diabetes mellitus has reached epidemic proportions. Progressive deterioration in glycaemic control and the current limitations of existing therapies such as weight gain and hypoglycaemia led us to welcome the first of a new class of drugs. Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a novel mode of therapy independent of insulin secretion or action. By blocking glucose reabsorption in the kidney they lead to an increase in urinary glucose excretion with reduction in plasma glucose levels.

Areas covered: In this article, we will review inhibition of SGLT2 as a novel strategy for the treatment of type 2 diabetes mellitus with dapagliflozin. PubMed and MEDLINE were searched for literature published up to July 2012, for efficacy, clinical effectiveness and safety reports of dapagliflozin.

Expert opinion: Improvement in glycaemic control with a low risk of hypoglycaemia, concomitant weight loss and the potential of lowering of blood pressure make SGLT2 inhibition an attractive approach using dapagliflozin therapy. Many SGLT2 inhibitors are undergoing Phase III clinical trials and more are in Phase I and II clinical trials.     

达格列净的合成

5-碘-2-氯-4'-乙氧基二苯甲烷与2,3,4,6-四-O-三甲基硅基-D-葡萄糖酸内酯经缩合、甲酯化和脱保护得到2-氯-5-(1-甲氧基-D-吡喃葡萄糖-1-基)-4'-乙氧基二苯甲烷,然后以三乙基硅烷-三氟化硼乙醚还原得达格列净粗品,粗品与乙酰氯酯化后,再水解得纯度99.9％的达格列净,总收率为40％.     

Combination therapy for type 2 diabetes: dapagliflozin plus metformin

Introduction: Type 2 diabetes (T2D) is a chronic and multifactorial metabolic disease, which brings great threats to public health. The morbidity of T2D keeps growing, and it is estimated that the population with T2D will rise to 552 million throughout the world by 2030. Effective glycemic control in patients is crucial for the treatment of T2D. However, with progressive deterioration of disease, most patients are usually unable to achieve glycemic targets receiving antidiabetic agent monotherapy. In such cases, combination therapy with different mechanisms of antidiabetic agents is highly desired. In addition, combination therapy can provide advantages beyond better glycemic improvement such as reduced incidence of hypoglycemia and cardiovascular events.

Areas covered: We reviewed all the published data regarding the fixed-dose combination therapy of dapagliflozin combined with metformin, including complementary mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy and safety.

Expert opinion: The fixed-dose combination of dapagliflozin and metformin exerts synergistic effects based on two antidiabetic agents with complementary mechanisms of action. Rational co-administration of dapagliflozin and metformin provides better glycemic control with potential weight loss and the reduced incidence of hypoglycaemia.     

钠-葡萄糖协同转运蛋白2抑制剂类抗糖尿病新药的研发概况

目前,钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂通过抑制葡萄糖在肾脏近曲小管的重吸收,从而成为治疗糖尿病的新途径。按其结构,SGLT2抑制剂主要分为C-芳基抑制剂、O-芳基抑制剂、S-糖苷抑制剂和N-糖苷抑制剂,而C-芳基抑制剂和O-芳基抑制剂处于研究热点,其中几个新药(dapagliflozin、canagliflozin、ASP1941、BI10773和LX4211)显示出良好的控制血糖水平和减轻体质量的效果,且不良反应较小。综述两类结构中的主要药物研究概况,并分析其研发前景。     

Sotagliflozin as a potential treatment for type 2 diabetes mellitus

Introduction: SGLT1 is the primary transporter responsible for the absorption of glucose and galactose in the intestine, while SGLT2 and SGLT1 are both involved in the renal reabsorption of glucose. SGLT2 inhibitors are a new class of oral antidiabetic drugs, acting by increasing urinary glucose excretion (UGE). They offer the advantages of a reduced risk of hypoglycaemia, a decrease in body weight and blood pressure and an efficacy at all stages of type 2 diabetes (T2DM).

Areas covered: Herein, the authors focus specifically on sotagliflozin (LX4211), the first-in-class dual SGLT1/SGLT2 inhibitor. Original publications in English were selected as the basis of this review. Clinical trials were identified using the Clinicaltrial.gov database.

Expert opinion: By a potential additional mechanism of action on intestinal glucose absorption linked to SGLT1 inhibition, sotagliflozin differentiates from SGLT2 inhibitors by reducing postprandial glucose excursion and insulin secretion, as well as by increasing GLP-1 secretion. Despite a weaker effect on UGE than selective SGLT2 inhibitors, sotagliflozin is as effective as SGLT2 inhibitors on HbA1C reduction, with a similar safety profile in short-term studies. While sotagliflozin was first assessed in T2DM, it is now in phase 3 development as an adjuvant treatment in patients with T1DM after positive results from a pilot study.     

Better response to the SGLT2 inhibitor dapagliflozin in young adults with type 2 diabetes

Background and aim: A variation of the response to Sodium glucose co-transporter 2 (SGLT2) inhibitors with age has not been investigated in patients with diabetes. The aim of this study was to assess renal threshold of glucose (RTg) before and after administration of an SGLT2 inhibitor in young adult patients (≤40 years) and older adult patients (>40 years) with type 2 diabetes (T2DM). Subjects and methods: Twenty Japanese patients with T2DM were enrolled. Baseline data were obtained on the first day and dapagliflozin (5 mg) was administered at 6:00 on the second day. Glucose excursions were assessed by continuous glucose monitoring and urine samples were collected every hour during the daytime (7:00 to 15:00) on both days. RTg was estimated from the regression line of the scatter plot of the hourly mean glucose concentrations. Results: After a single dose of dapagliflozin, RTg decreased from 121.5 to 6.1 mg/dl in the young adult group and from 151.0 mg/dl to ?15.8 mg/dl in the older group. After dapagliflozin, the slope of the regression line was significantly steeper in the young adult group. Conclusion: Dapagliflozin was more effective in young patients because they showed a larger response of urinary glucose excretion.     

Dapagliflozin: potential beneficial effects in the prevention and treatment of renal and cardiovascular complications in patients with type 2 diabetes

Introduction: Diabetic kidney disease is the leading cause of end-stage renal disease, a significant contributor to cardiovascular (CV) disease, responsible for much of the morbidity and mortality in patients with type 2 diabetes (T2DM). Strategies to slow or prevent the onset and progression of diabetic kidney disease are critical for effectively managing T2DM and reducing CV risk. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective antidiabetic agents, which may provide nephroprotective and CV protective effects.

Areas covered: This review examines the role of the kidney in glucose homeostasis, discusses renal hemodynamic changes in diabetes, and outlines the major hypotheses regarding the mechanisms underlying renal injury in diabetes. The potential benefits of SGLT2 inhibitors in the prevention and treatment of CV complications in patients with T2DM are reviewed, with particular focus on dapagliflozin.

Expert opinion: Dapagliflozin and other SGLT2 inhibitors have the capacity to decrease hyperglycemia and visceral fat, components of the metabolic syndrome particularly associated with the progression of CV disease. However, the mechanisms of action of SGLT2 inhibitors resulting in their positive CV effects remain unclear. Furthermore, the mechanism of action of SGLT2 inhibitors on heart function in non-diabetic patients with decompensated heart failure remains to be explored.     

SGLT2抑制剂治疗糖尿病研究进展

近年来,钠-葡萄糖协同转运蛋白2(type 2 sodium glucose co-transporters,SGLT2)抑制剂作为一种新型的治疗糖尿病药物成为研究热点。SGLT2在肾近端小管葡萄糖重吸收中起着非常重要的作用;抑制肾脏SGLT2可以促进Ⅱ型糖尿病人尿糖的排泄,使其血糖恢复正常而不会有低血糖的风险。临床实验表明,SGLT2抑制剂对Ⅱ型糖尿病的治疗效果明显,且具有降低体重、无低血糖风险等优点,目前,许多SGLT2抑制剂已经进入临床评价后期。     

Empagliflozin for the treatment of type 2 diabetes

Introduction: Despite the availability of numerous anti-diabetes drugs and treatment guidelines, many patients with type 2 diabetes mellitus (T2DM) do not reach recommended targets for glycemic control. There remains an unmet need for effective and well-tolerated anti-diabetes agents that can be used as monotherapy or in combination with other therapies to improve glycemic control in patients with T2DM. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of treatment for T2DM that reduce hyperglycemia by reducing renal glucose reabsorption and thereby increasing urinary glucose excretion.

Areas covered: This paper reviews the pharmacokinetic and pharmacodynamic properties of the SGLT2 inhibitor empagliflozin, the results of clinical trials investigating the efficacy of empagliflozin given as monotherapy or as add-on therapy on glycemic control, body weight, and blood pressure in patients with T2DM, and the safety and tolerability profile of empagliflozin.

Expert opinion: Empagliflozin offers good glycemic efficacy, weight loss, blood pressure reduction, and a low risk of hypoglycemia. These attributes, coupled with the ability to be used in virtually any combination with other anti-diabetes agents and at any stage in the disease process, provide a welcome new agent to our armamentarium of drugs to help manage T2DM.     

达格列净联合胰岛素治疗特定2型糖尿病住院患者的疗效与安全性分析

目的：探讨达格列净联合胰岛素治疗超重/肥胖、胰岛功能受损且血糖控制不佳的2型糖尿病住院患者的疗效与安全性。方法：对2017年7月1日－2018年6月30日收治于我院的55例2型糖尿病患者进行回顾性分析,根据用药方案分为对照组30例及达格列净组25例。对照组给予包括口服降糖药及胰岛素在内的降糖基础治疗,达格列净组给予降糖基础治疗+达格列净,观察至出院（约10 d）,比较2组间及治疗前后的疗效及安全性差异。结果：与对照组相比,达格列净组的胰岛素用量和达标时间显著降低（P<0.01）;住院第2、5天的空腹血糖和餐后2 h血糖显著降低（P<0.01）,住院第10天的体质指数（BMI）也显著降低（P<0.01）,降低程度与初始BMI呈正相关趋势。治疗期间2组患者均未发生严重不良反应,对照组发生轻微低血糖1例,达格列净组发生乏力1例,出院1个月后随访发现女性患者发生生殖系统感染2例和泌尿系统感染1例。结论：在降糖方案中加入达格列净用于超重/肥胖、胰岛功能受损且血糖控制不佳的2型糖尿病住院患者,能够快速起效降低血糖、缩短达标时间,显著降低BMI和胰岛素用量,女性患者需要密切监测有无生殖泌尿系感染的不良反应。     

Ertugliflozin as a monotherapy for the treatment of type 2 diabetes

ABSTRACT

Introduction: Sodium-dependent glucose transporter 2 (SGLT2) inhibitors are novel, potent oral anti-diabetic agents in a β-cell function-independent manner, inhibiting SGLT2-mediated renal glucose reabsorption and thus increasing urinary glucose excretion. Ertugliflozin (Steglatro^TM) is a new oral SGLT2 inhibitor for the treatment of patients with type 2 diabetes mellitus (T2DM) as a monotherapy or in combination with other anti-diabetic agents.

Areas covered: This review summarizes the collected data concerning the pharmacokinetics, clinical efficacy, as well as safety and tolerability profiles of ertugliflozin given as a monotherapy for the management of T2DM.

Expert opinion: Good glycemic control is crucial to the management of T2DM, and accordingly, anti-diabetic agents with various anti-hyperglycemic mechanisms are developed one after another. Based on the available clinical trials of ertugliflozin as a monotherapy for T2DM, it could be found that ertugliflozin effectively improves the glycemic control, body weight and blood pressure of patients with a low risk of hypoglycemia. It is also found that ertugliflozin moderately reduces their blood pressure, which is beneficial for decreasing the risk of cardiovascular disease. These attributes show the good potential of ertugliflozin as an adjunct treatment to diet and exercise for improving glycemic control in patients with T2DM.     

治疗糖尿病新药:钠-葡萄糖协同转运蛋白抑制剂dapagliflozin

钠-葡萄糖协同转运蛋白2(SGLT-2)是一种跨膜蛋白,主要分布在肾脏近曲小管,将葡萄糖从肾小管液转运入肾小管细胞内,约占肾脏重吸收葡萄糖的90%。SGLT-2抑制剂是治疗糖尿病的新药,可降低SGLT-2活性,减少肾脏对葡萄糖的重吸收量,增加尿糖排出,从而降低血糖。已有的临床试验表明SGLT-2抑制剂dapagliflozin治疗糖尿病有效且安全,患者耐受性良好。SGLT-2抑制剂很可能是未来糖尿病治疗的一个新的突破口。     

Pharmacoeconomic evaluation of sodium-glucose transporter-2 (SGLT2) inhibitors for the treatment of type 2 diabetes

Introduction: Clinicians have many safe and effective options for the treatment of type 2 diabetes that can improve glycemic control and effect other cardio-metabolic parameters. Sodium-glucose transporter-2 inhibitors (SGLT-2) are the most recent class of therapies, have a novel mechanism of action, and provide good glycemic efficacy and a favorable cardiovascular risk profile. Cost-effectiveness data can play an important role in assessing the benefits of this class of therapy in anti-diabetes treatment regimens.

Areas covered: This review summarizes all the available evidence regarding the cost-effectiveness of SGLT-2 inhibitors. For the purposes of this article, the authors have performed a systematic review of pharmacoeconomic analyses through a non-restricted literature until June 2018.

Expert opinion: The available analyses demonstrate that SGLT-2 inhibitors are a more cost-effective option compared to other oral anti-diabetes therapies and insulin in the treatment of individuals with uncontrolled type 2 diabetes. Future studies should examine populations with renal and liver disease and expand data of some SGLT-2 inhibitors to patients at high cardiovascular risk and hard endpoint data.     

新型抗2型糖尿病药物钠-葡萄糖协同转运蛋白2抑制剂研究进展

钠-葡萄糖协同转运蛋白（SGLT）是一类位于小肠黏膜（SGLT1）和肾近曲小管（SGLT2和SGLT1）中的葡萄糖转运基因家族。其中,SGLT2是一种低亲和力的转运蛋白,在肾脏中特异性表达并且在近曲小管葡萄糖重吸收中发挥非常重要的作用。它可以选择性地抑制SGLT2,即可通过增加尿糖的排出来治疗2型糖尿病,是一种创造性的治疗策略。本文介绍了SGLT2抑制剂在2型糖尿病治疗研究方面的最新进展,重点综述了SGLT2抑制剂的作用机制、部分在研SGLT2抑制剂的生物活性数据及临床试验结果。     

糖尿病治疗的新希望——SGLT2抑制剂

钠依赖的葡萄糖运载体(SGLTs)是一类在小肠黏膜和肾近曲小管中发现的转运基因家族,肾脏重吸收葡萄糖的过程主要由SGLTs介导。其中,SGLT1和SGLT2最为重要,SGLT2起主导作用。选择性地抑制SGLT2能显著降低机体对葡萄糖的重吸收,通过增加尿糖的排出从而降低血糖水平。SGLT2抑制剂是一种创造性的治疗策略,其作用靶点和机制与现有降糖药均不同,成为降糖药物研究的热点。文中介绍了SGLT2在调节血糖平衡中的作用,简单介绍了部分在研SGLT2抑制剂,重点综述了Ⅲ期临床药物dapagliflozin的临床试验结果。