Sodium Glucose CoTransporter 2 ( SGLT 2 ) Inhibitors in Type 2 Diabetes : A Literature Review of Approved Products

Diabetes mellitus continues to be a major health issue worldwide. Despite all of the treatment options available on the market, many patients with diabetes fail to reach their treatment goals. Novel agents such as the Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors show promise in effectively lowering blood glucose. Objective: To review the scientific literature for efficacy information regarding the use of approved SGLT2 inhibitors (canagliflozin, dapagliflozin and empagliflozin) in the treatment of Type 2 Diabetes Mellitus (T2DM). Methods: A MEDLINE (1950-August 2014) literature review was performed. All of the literature published as an original clinical trial was included in this review. Other pertinent articles published related to the original clinical trial were also included. Meta-analysis type studies were not selected for this review. Conclusions: With an increasing prevalence and incidence of type 2 diabetes mellitus worldwide, there is an apparent need for effective therapeutic strategies to combat this chronic and progressive disease. SGLT2 inhibitors offer this potential. Recently approved agents (canagliflozin, dapagliflozin and empagliflozin) have shown significant promise as monoand add-on therapy to current glucose-lowering regimens that may not otherwise be providing sufficient glycemic control in T2DM patients.


Introduction
Diabetes mellitus continues to be a major health issue worldwide, affecting nearly 26 million adults in the United States.Controlling blood glucose levels is essential in managing symptoms and preventing complications associated with the disease.In 2011, close to 85% of US adults with diabetes reported taking antihyperglycemic medication [1].
Despite all the treatment options available on the market, many patients with diabetes fail to reach their treatment goals.Most of these medications depend on the presence or action of insulin to exert their therapeutic effect.This can provide little benefit to patients whose disease progression has led to deterioration in pancreatic beta cell function.Additionally, these agents are associated with concerning side effects, including the risk of inducing hypoglycemia [2]- [4].
A new class of agents has emerged with glycemic control via alternate means, specifically by inhibiting the reabsorption of glucose and increasing its excretion from the kidneys.This novel approach of the Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors shows promise in effectively lowering blood glucose in a noninsulindependent way.Sodium-Glucose Cotransporter 2 inhibitors exert their effect by enhancing renal glycosuria.The extent to which they induce glycosuria is dependent on the plasma glucose concentration.As a result, blood glucose levels cannot be lowered below physiological levels and hence, the risk of hypoglycemia is not concerning [5].This mechanism of action allows use as monotherapy or in combination with current antidiabetes medications, including insulin therapy [2]- [4].Sodium-Glucose Cotransporter 2 inhibitors have also been shown to promote weight loss at the same time, either independently or in combination with other antidiabetic agents.However they have a risk of potentially increasing the likelihood of genitourinary tract infections [6].
The United States Food and Drug Administration (FDA) recently approved three SGLT2 inhibitors, canagliflozin in 2013, dapagliflozin and empagliflozin in 2014.This article discusses the SGLT2 inhibitors as new approaches to managing type 2 diabetes mellitus (T2DM), focusing on the evidence available regarding the efficacy and safety of this emerging class of antidiabetic agents.Canagliflozin, dapagliflozin, and empagliflozin were selected for this review since they are the only agents currently approved by the FDA.

Data Sources
Figure 1 illustrates the literature search and selection process details used in the identification of clinical trials for this review.A literature review was performed in MEDLINE (1950-August 2014) using the keywords diabetes mellitus type 2 AND canagliflozin OR dapagliflozin OR empagliflozin.The references identified from the literature review were then evaluated.All of the literature retrieved from MEDLINE that was published as an original clinical trial was included in this review.Other pertinent articles published related to the original clinical trials were also considered.Meta-analysis type studies were not selected for this review.References included in this review were limited to studies conducted in humans and written in the English language.All of the literature published as an original clinical trial in english and with human subjects was included in this review.
Other pertinent articles published related to the original clinical trial were also included.
Meta-analysis type studies were not selected for this review.

Canagliflozin
Canagliflozin, (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate, the first SGLT2 inhibitor approved in the United States, has an oral bioavailability of 65%, which remains the same with or without food.However, it is recommended to be taken before the first meal of the day due to its mechanism of reducing postprandial glucose excursions.Peak plasma concentrations are reached within one to two hours post-dose with a terminal half-life of 10.6 hours and 13.1 hours for the respective 100 mg and 300 mg doses.Canagliflozin exhibits extensive protein binding (99%), mainly to albumin, which does not affect plasma concentrations.It is metabolized primarily through O-glucuronidation and marginally through CYP3A4 (7%), and is excreted through fecal and renal routes.Though renal impairment may lead to a change in maximum plasma concentration (C max ) and area under the curve (AUC), these changes are not clinically relevant.However, since canagliflozin works by reducing glucose reabsorption in the kidney, pharmacodynamic response to the drug declines as the severity of renal impairment increases.Therefore, it is contraindicated in severe renal impairment, end stage renal disease, or patients on dialysis.According to Child-Pugh class grading, mild and moderate hepatic impairment do not warrant dose adjustments with canagliflozin [4].
The overall incidence of adverse events was similar between canagliflozin and control group treatment, however more patients withdrew related to canagliflozin adverse events.Since the SGLT2 inhibitors work by increasing the amount of glucose in the urine, there is a risk of urinary and genital tract infections unique to this class.Adverse events such as pollakiuria, polyuria, and volume-related effects, including postural dizziness and orthostatic hypotension, were more common in canagliflozin groups [7]- [16].

Dapagliflozin
Dapagliflozin, D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1) [2], was rejected by the FDA in January 2012 due to concerns about the cancer risk seen in studies [17].However, after reviewing more data on its safety profile, dapagliflozin was approved by the FDA in early 2014.The pharmacokinetic and pharmacodynamic properties of dapagliflozin are similar to canagliflozin.Dapagliflozin can be administered without regard to food.The oral bioavailability of dapagliflozin 10 mg is 78%.Maximum plasma concentration is usually reached within two hours in a fasting state and administration with a high-fat meal decreases the C max by up to 50% without altering the AUC, but is not clinically significant.The terminal half-life is approximately 12.9 hours following a dose of 10 mg.Dapag-  liflozin is 91% protein bound, which is unchanged in patients with renal or hepatic impairment.It is metabolized primarily by UGT1A9 with minor CYP-activity and is eliminated mainly through the kidneys.At steady state, T2DM patients with mild, moderate, or severe renal impairment (determined by estimated glomerular filtration rate (eGFR)) experience 45% to 3-fold higher systemic exposure of the drug without a corresponding higher 24-hour urinary glucose excretion.The steady state 24-hour urinary glucose excretion is 42% -90% lower in these patients [2].Dapagliflozin is not recommended in patients with moderate renal impairment as improvement in glycemic control was not seen in this population.Additionally, dapagliflozin is not expected to be effective in patients with severe renal impairment or end stage renal disease (ESRD).Dapagliflozin is contraindicated in these populations along with patients on dialysis.According to Child-Pugh class grading, mild, moderate, and severe hepatic impairment do not warrant dose adjustments with dapagliflozin, but the risk-benefit for use in patients with severe impairment should be individually assessed as the safety and efficacy have not been specifically studied in this population [2].
The majority of studies found a statistically significant decrease with mean FPG in dapagliflozin treatment groups compared to control groups [18]- [23] [25] [26] [28].Three of the four studies that assessed 2-h PPG after an oral glucose tolerance test (OGTT) found statistically significant decreases in dapagliflozin groups compared to control groups [19] [25] [26].Although [27] did not report statistical significance, 2-h PPG was found to be lower in the dapagliflozin groups.All studies found a greater decrease in body weight after treatment with dapagliflozin compared to the control [18]- [28].

Empagliflozin
Approved by the FDA in August 2014, empagliflozin, D-Glucitol,1,5-anhydro- ), is the newest SGLT2 inhibitor to enter the market.Similar to the other available agents, empagliflozin is approved for use in T2DM patients, as an adjunct to diet and exercise [3].Plasma concentrations peak at approximately 1.5 hours post-oral administration [3] [29] with a reduction in AUC (16%) and C max (37%) when taken after a high-fat and high-calorie meal.Although reductions in systemic exposure were noted, the impact on clinical outcomes was not deemed significant.As a result, empagliflozin may be taken with or without food.Empagliflozin has a plasma protein binding of roughly 86%.Metabolism occurs primarily via glucuronidation with minimal metabolite exposure.The terminal half-life of empagliflozin is 12.4 hours.Empagliflozin is primarily eliminatedrenally.Increases in AUC have occurred in patients with renal impairment, kidney failure or ESRD.Empagliflozin is contraindicated in severe renal impairment, ESRD, or dialysis [3].
The impact on plasma concentration varies based on the degree of renal and hepatic impairment.Patients with moderate renal impairment, kidney failure, or ESRD have peak plasma concentrations comparable to patients

Conclusion
Considering the increasing prevalence and incidence of type 2 diabetes mellitus worldwide, there is an obvious need for effective therapeutic strategies to combat this chronic and progressive disease.The need for agents with novel mechanisms of action is becoming more and more crucial owing to the need for individualized glycemic targets and glucose-lowering therapies, concerning side effects of many current therapies, and the progressive β-cell function decline associated with T2DM.SGLT2 inhibitors offer this potential and recently approved canagliflozin, dapagliflozin, and empagliflozin have shown significant promise as mono-and add-on therapy to current glucose-lowering regimens that may not otherwise be providing sufficient glycemic control in T2DM patients.Short-term benefits have certainly been made clear through the variety of clinical trials performed on these drugs, however there is still a need to establish long-term safety and efficacy.The significance of the unique side effects of increased genital mycotic infections and associated adverse events must also be considered.Several other agents in this class are in phase III trials and show similar promise in their efficacy as addon treatments.

Figure 1 .
Figure 1.Literature search and clinical trial selection details.