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.     

The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes

Introduction: There is now an abundance of anti-diabetic agents. However, only few patients achieve glycemic targets. Moreover, current glucose-lowering agents mainly depend upon insulin secretion or function. Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion.

Areas covered: In this review, the authors discuss the key efficacy and safety data from phase II clinical trials in type 2 diabetes mellitus (T2DM) of the main SGLT2 inhibitors approved or currently in development, and provide a rationale for their use in T2DM.

Expert opinion: Despite the very promising characteristics of this new therapeutic class, a number of issues await consideration. One important question is what to expect from head-to-head comparison data. We also need to know if dual inhibition of SGLT1/SGLT2 is more efficacious in reducing HbA_1c and how this therapy affects metabolic and cardiovascular parameters. Additionally, several SGLT2 agents that have not yet come to market have hitherto been evaluated in Asian populations, whereas approved SGLT2 inhibitors have been frequently studied in other populations, including Caucasian subjects. Thus, we need more information on the potential role of ethnicity on their efficacy and safety.     

SGLT2 inhibitors: a new emerging therapeutic class in the treatment of type 2 diabetes mellitus

The incidence of type 2 diabetes mellitus is increasing worldwide. The existing therapeutic classes of antidiabetic drugs are not adequately effective in maintaining long-term glycemic control in most patients, even when used in combination. One emerging novel therapeutic class of antidiabetic drugs is sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 accounts for 90% of the glucose reabsorption in the kidney. The SGLT2 inhibitors increase urinary excretion of glucose and lower plasma glucose levels in an insulin-independent manner. Dapagliflozin, the most prominent molecule in this class, is currently in a phase III clinical trial. Other members of this class (eg, sergliflozin, remogliflozin) are also in different phases of clinical trials. This class of novel agents can effectively control blood sugar level without producing weight gain or hypoglycemia. Results of ongoing phase III clinical trials are crucial to determine whether the risk-benefit ratio will allow approval of this new class of drugs for the management of type 2 diabetes mellitus.     

Luseogliflozin and other sodium-glucose cotransporter 2 inhibitors: no enemy but time?

Glycosuria is being increasingly recognised as not only a symptom but also as a novel therapeutic approach in the management of type 2 diabetes mellitus (T2DM). This is accomplished through sodium glucose co-transporter 2 (SGLT2) inhibitors. Consequently, the safety and efficacy of these new agents have been thoroughly studied, both in randomised controlled trials and in systematic reviews and meta-analyses. More recently, a review on the mechanism of action, clinical efficacy and safety of luseogliflozin, a new highly selective SGLT2 inhibitor approved and launched in Japan for T2DM, has documented that this drug lowers plasma glucose concentration and body weight, and that it exhibits benefits in other metabolic parameters with a good safety profile. Despite the promising characteristics of this drug, important issues await consideration. These include the question as to when and to whom early use of SGLT2 inhibitors would be most suitable, as well as instructions on reduction of sulfonylurea dosage during add-on treatment. Further important questions are long-term safety concerns and cost-effectiveness of this new therapeutic class. Finally, we need to know more about the potential differences between the various SGLT2 inhibitors, as such differences might prove clinically useful in selection of hypoglycaemic agents.     

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.     

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.     

Practical considerations for the use of sodium–glucose co-transporter type 2 inhibitors in treating hyperglycemia in type 2 diabetes

Sodium–glucose co-transporter type 2 (SGLT2) inhibitors are a new class of oral anti-diabetic agents with a unique, insulin-independent mode of action. In patients with diabetes who have adequate renal function, SGLT2 inhibitors reduce hyperglycemia by blocking renal glucose reabsorption and increasing urinary glucose excretion. These agents are indicated for the treatment of hyperglycemia in type 2 diabetes mellitus (T2DM), as an adjunct to diet and exercise. In terms of efficacy, they are comparable to most other oral agents, and carry a low risk of hypoglycemia unless combined with sulfonylureas or insulin. They may be used in combination regimens with metformin, sulfonylureas, or insulin. Beyond glucose lowering, SGLT2 inhibitors are associated with modest weight loss and mild anti-hypertensive effects. Emerging cardiovascular and renal outcomes data suggest other potentially beneficial non-glycemic effects, although these findings await confirmation from further studies. The main adverse effects are increased risk of volume depletion and of genitourinary infections, although these can be managed with standard interventions. Rare cases of euglycemic ketoacidosis have been reported in a subset of patients treated with these agents, an issue currently under investigation. SGLT2 inhibitors represent a promising alternative treatment option for T2DM patients in whom the effectiveness of oral anti-hyperglycemic therapy is limited by the risk of hypoglycemia, weight gain, or other adverse effects. Safety and efficacy (up to 4 years) have been demonstrated in a range of T2DM patient populations, although more studies will be needed to determine whether treatment with SGLT2 inhibitors improves patient-important outcomes in the longer term.     

An update of SGLT1 and SGLT2 inhibitors in early phase diabetes-type 2 clinical trials

Introduction: More than 424 million adults have diabetes mellitus (DM). This number is expected to increase to 626 million by 2045. The majority (90–95%) of people with DM has type 2-diabetes (T2DM). The continued prevalence of DM and associated complications has prompted investigators to find new therapies. One of the most recent additions to the anti-diabetic armamentarium are inhibitors of sodium-glucose co-transporters 1 and 2 (SGLT1, SGLT2).

Areas covered: The authors review the status of SGLT2 inhibitors for the treatment of T2DM and place an emphasis on those agents in early phase clinical trials. Data and information were retrieved from American Diabetes Association, Diabetes UK, ClinicalTrials.gov, PubMed, and Scopus websites. The keywords used in the search were T2DM, SGLT1, SGLT2, and clinical trials.

Expert opinion: The benefits of SGLT inhibitors include reductions in serum glycated hemoglobin (HbA1c), body weight, blood pressure and cardiovascular and renal events. However, SGLT inhibitors increase the risk of genitourinary tract infections, diabetic ketoacidosis, and bone fractures. The development of SGLT inhibitors with fewer side effects and as combination therapies are the key to maximizing the therapeutic effects of this important class of anti-diabetic drug.     

二肽基肽酶4抑制剂和钠-葡萄糖转运蛋白2抑制剂 联合治疗2型糖尿病的临床应用进展

DPP-4抑制剂与SGLT2抑制剂联合治疗,可以在减轻副作用的基础上更加有效地降低2型糖尿病患者的血糖,但是对于不同剂量的组合,仍需大量临床试验以评估其临床疗效和安全性,使临床医生根据T2DM病人的具体情况选择治疗药物的组合。     

SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus

Background Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose reabsorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications. Sodium glucose cotransporter 2 (SGLT2) has a key role in reabsorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes. Objective To discuss the therapeutic potential of SGLT2 inhibitors currently in clinical development. Key findings A number of preclinical and clinical studies of SGLT2 inhibitors have demonstrated a good safety profile and beneficial effects in lowering plasma glucose levels, diminishing glucotoxicity, improving glycemic control and reducing weight in diabetes. Of all the SGLT2 inhibitors, dapagliflozin is a relatively advanced compound with regards to clinical development. Summary SGLT2 inhibitors are emerging as a promising therapeutic option for the treatment of diabetes. Their unique mechanism of action offers them the potential to be used in combination with other oral anti‐diabetic drugs as well as with insulin.     

钠-葡萄糖共转运蛋白2抑制剂治疗2型糖尿病的临床研究进展

2 型糖尿病是一种以胰岛素分泌缺陷、胰岛素抵抗或者两者并存所致的高血糖为特征的慢性代谢性疾病。早期血糖控制不佳可以促进微血管并发症的进展,以及大血管风险的发生。虽然有众多的降糖药物在临床使用,但只有约50%的患者能实现血糖控制,传统药物仍存在某些不足,因此,需要开发具有新机制的治疗药物。钠-葡萄糖共转运蛋白2（SGLT2）是近年来发现的具有全新作用机制的一个糖尿病治疗靶点。SGLT2 抑制剂通过抑制肾脏近端小管对葡萄糖的重吸收来增加尿中葡萄糖的排泄而达到控制血糖的目的,其独立于葡萄糖依赖的胰岛素途径,能使低血糖发生风险降低。临床试验数据表明,SGLT2 抑制剂单药治疗和与传统降糖药物联合治疗均可以有效地控制血糖,并改善胰岛素抵抗,同时也有降血压和减少体质量作用。尽管后续的研究显示了SGLT2 抑制剂具有良好的耐受性,该类药物在临床上报道的意想不到的风险仍需要大量和长期的临床数据证实。     

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.     

Short-term impacts of sodium/glucose co-transporter 2 inhibitors in Japanese clinical practice: considerations for their appropriate use to avoid serious adverse events

Sodium/glucose co-transporter 2 inhibitors (SGLT2i) represent a novel class of glucose-lowering agents that lower plasma glucose levels through pharmacological inhibition of glucose reuptake from the kidney, independent of insulin secretion and action. Clinical trials of SGLT2i demonstrated therapeutic benefits on glycemic control and bodyweight in individuals with type 2 diabetes, with few cases of serious adverse events (SAEs). However, a considerable number of SAEs were reported in patients receiving SGLT2i clinically in Japan during the first 3 months of their use. These included urogenital infections, hypoglycemia and dehydration. Unexpectedly, serious skin and subcutaneous disorders, mainly reported as generalized rash or skin eruption, were prominent in patients receiving SGLT2i, but with unknown mechanisms. There is also concern for potential SAEs associated with chronic SGLT2i administration, especially in the non-obese type 2 diabetes characterized by reduced insulin secretion often seen in East Asia. Chronic SAEs may include severe hypoglycemia due to depletion of hepatic glycogen storage, acceleration of diabetes-associated sarcopenia and ketosis/ketoacidosis. The current information on acute SAEs confirms the importance of caution in the appropriate use of SGLT2i. Furthermore, careful long-term observation of patients receiving SGLT2i is essential to avoid SAEs and for better clinical use of this drug class.     

Effectiveness and safety of sodium–glucose co-transporter-2 inhibitors in Thai adults with type 2 diabetes mellitus: a real-world study

Abstract

Background

Sodium–glucose co-transporter-2 inhibitors (SGLT2is) are widely used to improve both glycemic control and cardio-renal outcomes. We aim to evaluate the real-life clinical effectiveness, safety and outcomes of SGLT2is in Thai adults with type 2 diabetes mellitus (T2DM).     

Evaluation of vulvovaginal symptoms and Candida colonization in women with type 2 diabetes mellitus treated with canagliflozin,a sodium glucose co-transporter 2 inhibitor

Abstract

Background/objective:

Women with type 2 diabetes mellitus (T2DM) are at increased risk for vaginal Candida colonization, perhaps because of glucosuria. Sodium glucose co-transporter 2 (SGLT2) inhibitors, in development for the treatment of T2DM, improve glycemic control by increasing urinary glucose excretion. Vaginal Candida colonization and symptomatic vulvovaginal adverse events (VVAE) were assessed in females with T2DM treated with canagliflozin, a SGLT2 inhibitor.     

An emerging new concept for the management of type 2 diabetes with a paradigm shift from the glucose-centric to beta cell-centric concept of diabetes - an Asian perspective

ABSTRACT

Introduction

Recent advances in anti-diabetic medications and glucose monitoring have led to a paradigm shift in diabetes care. Newer anti-diabetic medications such as DPP-4 inhibitors, GLP-1 receptor agonists (GLP-1RAs), and SGLT2 inhibitors have enabled optimal glycemic control to be achieved without increasing the risk of hypoglycemia and weight gain. Treatment with GLP-1RAs and SGLT2 inhibitors has been demonstrated to improve cardiorenal outcomes, positioning these agents as the mainstay of treatment for patients with type 2 diabetes (T2DM). The development of these newer agents has also prompted a paradigm shift in the concept of T2DM, highlighting the importance of beta cell dysfunction in the pathophysiology of T2DM.     

Dapagliflozin: an emerging treatment option in type 2 diabetes

The global incidence of type 2 diabetes mellitus is increasing. Hyperglycemia contributes to both the complications associated with diabetes mellitus and progression of the underlying disease. New agents that lower blood glucose levels are therefore needed to help slow disease progression and reduce disease complications. The sodium-glucose co-transporter 2 (SGLT2) reabsorbs glucose in the kidney. Inhibition of SGLT2 by new agents, such as dapagliflozin, has the potential to reduce hyperglycemia by inhibiting glucose reabsorption in the kidney. Preclinical trials demonstrated that dapagliflozin is a potent and selective inhibitor of SGLT2. It has shown linear pharmacokinetics over the dose range of 2.5 – 500 mg/day, is not significantly influenced when taken with food and is primarily eliminated via urinary excretion. Clinical trials have shown that dapagliflozin treatment induces glucosuria and improves glycemic parameters in patients with type 2 diabetes. Inhibition of SGLT2 is a new and promising approach to treating type 2 diabetes mellitus. This article reviews the role of dapagliflozin as an emerging treatment option in type 2 diabetes.     

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.     

Luseogliflozin for the treatment of type 2 diabetes

Introduction: Sodium glucose cotransporter 2 (SGLT2) inhibitors are expected to provide adequate glycemic control, and be safe and well tolerated, for treating type 2 diabetes mellitus (T2DM). Luseogliflozin is a highly selective SGLT2 inhibitor that was recently approved for marketing and launched in Japan to treat T2DM.

Areas covered: This review summarizes the published data regarding the mechanism of action, clinical efficacy, and safety of luseogliflozin for treating T2DM. Other potential benefits of luseogliflozin, including lowering body weight and blood pressure, beyond its glucose-lowering effects are also discussed.

Expert opinion: Luseogliflozin lowers plasma glucose concentration and body weight, and has beneficial effects on other clinically relevant parameters, including blood pressure and uric acid, in patients with T2DM. Although it had a good safety profile in clinical trials, there may be some safety concerns, including a possible decrease in muscle mass and an increase in ketone bodies. Therefore, careful administration and consideration of its benefit–risk balance are necessary. When using luseogliflozin, it is important to select appropriate patients and to adhere to its guidelines for use. If used correctly, luseogliflozin is expected to be positioned as a new type of oral hypoglycemic drug for treating T2DM.