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.     

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.     

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.     

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.     

Efficacy and safety profile of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease

ABSTRACT

Introduction: Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) have a complex relationship with the kidney so that their use in patients with type 2 diabetes (T2DM) and diabetic kidney disease (DKD) has long been challenged.

Areas covered: SGLT2is in patients with DKD are discussed: renal mechanisms of action, PK/PD characteristics, clinical use in patients with stage 3 DKD, effects on estimated glomerular filtration rate (eGFR) and albuminuria, cardiovascular, and renal outcomes according to renal function, overall and renal safety, SGLT2is new place in updated guidelines.

Expert opinion: Whereas initial concerns (reduced glucose-lowering efficacy, early reduction in eGFR) led to restrictions in the use of SGLT2is in patients with DKD, recent positive observations have completely reversed the scene. Indeed, albuminuria is reduced and eGFR is preserved in the long term by SGLT2is. A significant reduction in cardiovascular events and hard renal outcomes was reported even in patients with eGFR 30–60 mL/min/1.73 m². The overall safety profile of SGLT2is is not altered in patients with mild to moderate DKD, with a reduced (rather than increased) risk of acute renal injury. This positive benefit/risk balance led recent guidelines to recommend SGLT2is in patients with T2DM and mild to moderate DKD, especially if albuminuria.     

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.     

An evaluation of US patent 2015065565 (A1) for a new class of SGLT2 inhibitors for treatment 1 of type II diabetes mellitus

Introduction: Type 2 diabetes mellitus (T2DM) is a growing and serious global health problem. Pharmacological inhibition of the sodium–glucose cotransporter-2 (SGLT2; SLC5A2) increases urinary glucose excretion, decreasing plasma glucose levels in an insulin-independent manner. Agents that inhibit SGLT2 have recently become available for clinical therapy of T2DM.

Areas covered: The patent claims a new class of SGLT2 inhibitors: derivatives of dioxa-bicyclo[3.2.1]octane-2,3,4-triol (including ertugliflozin; PF-04971729). The invention describes the design, synthesis and pharmacological tests related to ertugliflozin, which could ultimately lead to efficacious therapy for T2DM alone or in combination with other anti-diabetic agents.

Expert opinion: Ertugliflozin is likely to be of great clinical significance in the near future. Continued analysis of ertugliflozin derivatives to now validate safe and efficacious treatment of T2DM in a larger number of clinical subjects over an extended period is needed to further support clinical utility. Identification, and discussion, of likely contra-indications is also needed.     

Network meta-analysis of treatments for type 2 diabetes mellitus following failure with metformin plus sulfonylurea

Aims The efficacy and safety of sodium–glucose linked transporters (SGLT2s) plus metformin and a sulfonylurea (MET?+?SU) for the treatment of type 2 diabetes mellitus (T2DM) in patients who fail to achieve glycemic control with MET?+?SU, relative to other triple therapies licensed in the EU, were estimated.

Methods A systematic literature review and network meta-analysis (NMA) of randomized controlled trials (RCTs) involving anti-diabetes treatments added to MET?+?SU were conducted.

Results: Of 2236 abstracts identified through a systematic literature review, 30 RCTs published between 2003 and 2013 were included. RCTs ranged from 12 to 52 weeks in duration, included 28 to 1274 patients, were of parallel design, and most were open-label. Comparators included placebo (reference treatment), SGLT2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), alpha-glucosidase inhibitors (AGIs), meglitinides, glucagon-like peptide 1 (GLP-1) analogues, and basal, bolus, and biphasic insulin, all added on to MET?+?SU, as well as basal and biphasic insulin added to MET and monotherapy. The mean change (%) in HbA1c levels compared to placebo was -0.86 for SGLT2 inhibitors, ?0.68 for DPP-4 inhibitors, ?0.93 for TZDs, and ?1.07 for GLP-1 analogues, respectively. Only SGLT2 inhibitors and GLP-1 analogues led to a weight loss (?1.71 kg and ?1.14 kg, respectively) and decrease in systolic blood pressure (SBP; ?3.73 mmHg and ?2.90 mmHg, respectively), while all other treatments showed either an increase or no changes in weight or SBP.

Conclusion SGLT2 inhibitors are at least as effective as other classes of antidiabetic agents at controlling HbA1c levels, while providing the additional benefits of weight loss and reducing SBP. Additionally, since the risk of hypoglycemia is similar or reduced with SGLT2 inhibitors, patients do not have to trade off efficacy for tolerability. Similar findings were observed for GLP-1 analogues.     

Preventing and treating kidney disease in patients with type 2 diabetes

Introduction: Chronic kidney disease (CKD) represents a huge burden in patients with type 2 diabetes (T2DM). This review therefore has the aim of assessing the add-on value of new glucose-lowering agents compared or combined with inhibitors of the renin angiotensin aldosterone system (RAAS) on renal outcomes in T2DM patients.

Areas covered: This article first summarizes the results reported with RAAS inhibitors, mainstay of nephroprotection in T2DM with albuminuria. Second, it describes the positive results with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and, even more impressive, sodium-glucose cotransporter type 2 inhibitors (SGLT2is). Third, besides the potential of combined therapies, it briefly considers some new approaches currently in development.

Expert opinion: RAAS inhibitors exert renoprotective effects beyond their blood pressure lowering effects while SGLT2is, and possibly GLP-1RAs, exert nephroprotection independently of their glucose-lowering activity. These effects were demonstrated not only on surrogate endpoints such as albuminuria and estimated glomerular filtration rate decline, but also on hard endpoints, including progression to end-stage renal disease requiring replacement therapy. The underlying mechanisms are different and potentially complementary on glomerular hemodynamics, arguing for combined therapies. Nevertheless, there is still room for new emerging drugs to tackle CKD in T2DM.     

SGLT2 inhibitors for the treatment of diabetes: a patent review (2013-2018)

Introduction: The sodium-glucose co-transporter 2 (SGLT2) is ascribed to target renal tubular glucose re-absorption, and its inhibition has been proved to induce glucosuria which improves the glycemic index. Accordingly, SGLT2 inhibitors have found to be the promising class of antidiabetic agents for the management of type 2 diabetes mellitus. A large number of SGLT2 inhibitors have developed through structural modification and investigated for their ability to selectivity inhibit SGLT2 transporters with better bioavailability.

Areas covered: This review comprises a summary of patent applications (2013–2018) of SGLT2 inhibitors with focus on chemical structural advancement and therapeutic potentials in the management of diabetes and related disorders.

Expert opinion: SGLT2 inhibitors exert multiple metabolic benefits, including reduced glycated hemoglobin (HbA1c), improved glycemic control (fasting and postprandial), reduced body weight, reduced systolic and diastolic blood pressure and improved HDL cholesterol. Due to the virtue of no interference with insulin action and secretion, their efficacy remains the same even in presence of progressive β cell failure in type 2 diabetes. Additionally, few members of this class have been reported to exhibit cardioprotective, renoprotective, and anticancer activity. However, more study on the long-term outcomes in patients taking SGLT2 inhibitors is warranted.     

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.     

From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus

ABSTRACT

Background: Elevated glucose blood levels are the key criteria for diagnosing diabetes mellitus (DM). Hyperglycaemia contributes to the pathophysiology associated with DM, including microvascular and possibly macrovascular disease. In spite of a wide range of pharmacological options available to reduce hyperglycaemia in DM, epidemiological studies suggest that glucose levels remain high in a substantial proportion of patients. This supports the need for additional strategies for the treatment of hyperglycaemia.

Scope: This review focuses on the role of the kidney in glucose reabsorption and explores inhibition of renal glucose reabsorption as a novel approach to treat type 2 DM. A literature search to August 2008 using PubMed was used to compile data for review. Abstracts and presentations from the American Diabetes Association and the European Association for the Study of Diabetes, the American Society of Nephrology, and the International Society of Nephrology Annual Meetings were also searched for relevant studies.

Findings: Glucose filtered by the kidney is normally reabsorbed into the proximal renal tubule. Data from animal models suggest that approximately 90% of this reabsorption occurs through the sodium-coupled glucose cotransporter (SGLT) 2, which is a protein expressed almost exclusively in the proximal tubule of the kidney. Inhibition of SGLT2, and thus inhibition of renal glucose reabsorption, has the potential to reduce hyperglycaemia in patients with DM. Patients with familial renal glucosuria, a genetic disorder of SGLT2, do not appear to have adverse clinical consequences related to impaired renal reabsorption of glucose, which suggests that SGLT2 might be both an effective and safe treatment target for hyperglycaemia. In animal models of DM, pharmaceutical inhibition of SGLT2 reduces hyperglycaemia, and may improve insulin resistance.

Conclusion: Reduction of renal glucose reabsorption is a novel approach to DM treatment that potentially provides improvements in glucose lowering. Various SGLT2 inhibitors are currently in development in human trials.     

The safety of DPP-4 inhibitor and SGLT2 inhibitor combination therapies

Introduction: Type 2 diabetes (T2D), a multifactorial and chronic disease, requires in an elevated percentage of patients the association of several antidiabetic drugs to achieve optimal glycemic control. Dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium–glucose cotransporter inhibitors (SGLT2i) are new classes of oral antidiabetic drugs developed over the last years.

Areas covered: This paper summarizes the safety of DPP-4i and SGLT2i combination therapies. Relevant studies were identified through searches in PubMed.

Expert opinion: DPP4i and SGLT2i are antidiabetic drugs that lower blood glucose without causing hypoglycaemia or weight increase. More importantly, cardiovascular trials have clearly demonstrated the cardiovascular safety of DPP4i and a reduction in cardiovascular events with SGLT2i (empagliflozin and canagliflozin). Therefore, the association of both therapeutic groups could be an attractive option to achieve optimal blood glucose control in T2D because of their complementary mechanism of action. Clinical trials evaluating the combination of SGLT2i and DPP4i show that the co-administration of these drugs in fixed-dose combinations in comparison to separate tablets does not carry additional safety concerns that each individual drug, but increases therapeutic effects. Therefore, this antidiabetic combination is a safe and effective therapy for patients with T2D.     

A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose cotransporter 2 inhibitors (SGLT2i) are of particular interest in type 2 diabetes treatment strategies, due to their efficacy in reducing HbA1c with a low risk of hypoglycaemia, to their positive effects on body weight and blood pressure and in light of their effects on cardiovascular risk and on nephroprotection emerged from the most recent cardiovascular outcome trials.

Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile.

Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes.

Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a ‘similar’ safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other.     

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 co-transporter 2 inhibitor luseogliflozin in the management of type 2 diabetes: a drug safety evaluation

Introduction: Sodium glucose co-transporter-2 (SGLT2) inhibitors have been developed recently as a new class of anti-diabetic drug, and are becoming widely used in the management of type 2 diabetes (T2D). As these agents have a considerably different glucose-lowering mechanism from those of other anti-diabetic drugs, safe use of this drug class needs to be discussed based on data available from preapproval clinical trials as well as real-world studies. The SGLT2 inhibitor luseogliflozin was developed by Taisho Pharmaceutical Co., Ltd. and was approved as an oral anti-diabetic drug for T2D in Japan

Areas covered: The overall safety and efficacy of SGLT2 inhibitor luseogliflozin are summarized on the basis of a literature review, with a focus on reported adverse drug reactions in preapproval clinical trials and a post-marketing surveillance.

Expert opinion: SGLT2 inhibitor luseogliflozin is well tolerated, significantly improves hyperglycemia in preapproval clinical trials, and has a favorable safety profile in both preapproval clinical trials and post-marketing surveillance in elderly patients. While long-term safety and efficacy remain to be seen, luseogliflozin can benefit T2D patients worldwide. However, healthcare professionals must perform appropriate patient education that includes temporary withdrawal of luseogliflozin during patient a ‘sick day’ and avoidance of strict carbohydrate restriction during luseogliflozin treatment.     

The importance of synthetic drugs for type 2 diabetes drug discovery

Introduction: Type 2 diabetes mellitus (T2DM) is a major metabolic, multi-causal and heterogeneous disorder which causes significant morbidity and mortality with considerable burden to healthcare resources. The number of deaths due to T2DM highlights the insufficiency of the currently available drugs for controlling the disease and its complications and more needs to be done.

Areas covered: This paper reviews the updated pathobiology of T2DM that should be targeted in drug discovery. Further, the article provides discussion on the mechanism of action, side effects and structure of the currently available synthetic drugs. The authors specifically evaluate two newer classes of anti-diabetic agents: dipeptidyl peptidase IV (DPP-4) and sodium-glucose transporter-2 (SGLT2). They also present information on newer synthetic compounds. The article also highlights the key interactions between synthetic compounds and DPP-4 active site residues for rational drug design.

Expert opinion: Numerous anti-hyperglycaemic drugs are currently available but many are limited by their adverse effects. The identification of the 3D structure of DPP-4 has opened new avenues for design, thus aiming to produce drugs that directly exploit the structural characteristics of this binding site. Further, structural- and ligand-based screening techniques have been developed for designing novel DPP-4 and SGLT2 inhibitors. There has also been progress with the design and development of novel T2DM therapeutics including: PPARα/ dual agonists, Sirtuin 1 activators, glycogen phosphorylase inhibitors and protein tyrosine phosphatase 1B inhibitors. Finding new targets and synthesis methods is still essential but it is becoming accepted that no diabetic therapy is ‘best suited' with each patient responding differently.     

Evaluating the costs of glycemic response with canagliflozin versus dapagliflozin and empagliflozin as add-on to metformin in patients with type 2 diabetes mellitus in the United Arab Emirates

Objective: This study evaluates the cost of achieving glycemic control with three sodium glucose co-transporter 2 (SGLT2) inhibitors, canagliflozin, dapagliflozin, and empagliflozin, in patients with type 2 diabetes mellitus (T2DM) from the payer perspective in the United Arab Emirates (UAE).

Methods: A systematic literature review identified randomized controlled trials of antihyperglycemic agents as add-on to metformin in patients with T2DM of 26?±?4 weeks in duration, published by 10 September 2014. A Bayesian network-meta analysis (NMA) compared HbA1c changes with canagliflozin 100 and 300?mg versus dapagliflozin 10?mg and empagliflozin 10 and 25?mg. The cost associated with a 1% placebo-adjusted HbA1c reduction with each SGLT2 inhibitor as add-on to metformin was calculated based on NMA results and UAE drug costs.

Results: In the NMA, canagliflozin 100 and 300?mg were associated with HbA1c reductions (?0.67% and ?0.79%) compared with dapagliflozin 10?mg (?0.41%) and empagliflozin 10 and 25?mg (?0.57% and ?0.64%). Probabilities of canagliflozin 100?mg performing better were 79%, 60%, and 53% versus dapagliflozin 10?mg and empagliflozin 10 and 25?mg, respectively; probabilities for canagliflozin 300?mg performing better were 88%, 72%, and 65%, respectively. The cost per 1%-point reduction in HbA1c was projected to be lower with canagliflozin 100 and 300?mg ($448 and $422) compared with dapagliflozin 10?mg ($785) and empagliflozin 10 and 25?mg ($527 and $563).

Conclusions: Canagliflozin may provide a greater glycemic response at a lower effective cost than dapagliflozin or empagliflozin for patients with T2DM inadequately controlled with metformin from the payer perspective in the UAE.     

Real-world impact of glycated hemoglobin reduction on treatment intensification and glycated hemoglobin goal attainment in type 2 diabetes mellitus patients initiated on a sodium glucose co-transporter 2 (SGLT2) inhibitor (SGLT2i)

Objective: To evaluate the impact of a 0.2% reduction in glycated hemoglobin (HbA1c) on treatment intensification, poor HbA1c control and HbA1c goal attainment in patients with type 2 diabetes mellitus (T2DM) initiated on a sodium glucose co-transporter 2 (SGLT2) inhibitor (SGLT2i).

Methods: IQVIATM Health Plan Claims Data – US and IQVIATM Ambulatory EMR Data – US databases (29 October 2012–31 March 2016) were used to identify adults with T2DM initiated on an SGLT2i (index date) who had HbA1c measurements pre- and post-index, and ≥6?months of eligibility pre-index (baseline). HbA1c change was defined as the difference between the first post-index and the last pre-index measurements. Cox regression models were used to assess treatment intensification, poor HbA1c control (i.e. HbA1c?>?9%, among patients <9% at baseline) and goal attainment (HbA1c?<?7%, <8%; among patients with HbA1c above goal at baseline) adjusting for HbA1c change and baseline characteristics. Patients were observed up to one year after the first HbA1c measurement or end of eligibility. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported.

Results: A total of 938 patients (mean age 54.9, 42.5% female, mean HbA1c 8.5%) were selected. Following SGLT2i initiation, each 0.2% reduction in HbA1c levels was associated with a decreased risk of treatment intensification (HR [95% CI]?=?0.90 [0.86–0.92]), a decreased likelihood of reaching HbA1c?>?9% (HR [95% CI]?=?0.85 [0.79–0.88]) and higher likelihoods of achieving a treatment goal of HbA1c?<?7% (HR [95% CI]?=?1.17 [1.12–1.21]) and HbA1c?<?8% (HR [95% CI]?=?1.08 [1.04–1.10]).

Conclusions: In T2DM patients, each HbA1c reduction of 0.2% following the initiation of an SGLT2i was associated with a significant positive impact on treatment intensification and HbA1c goal attainment.