Scholarly article on topic 'The role of the kidneys in glucose homeostasis in type 2 diabetes: Clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors'

The role of the kidneys in glucose homeostasis in type 2 diabetes: Clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — John P.H. Wilding

Abstract The kidneys play an important role in regulating glucose homeostasis through utilization of glucose, gluconeogenesis, and glucose reabsorption via sodium glucose co-transporters (SGLTs) and glucose transporters. The renal threshold for glucose excretion (RTG) is increased in patients with type 2 diabetes mellitus (T2DM), possibly due to upregulation of SGLT2 and SGLT1 expression. The resulting increase in renal glucose reabsorption is thought to contribute to the maintenance of hyperglycemia in patients with T2DM. Selective SGLT2 inhibitors reduce the RTG, thereby increasing glucosuria, and have demonstrated favorable efficacy and safety in patients with T2DM inadequately controlled with diet and exercise and other glucose-lowering treatments.

Academic research paper on topic "The role of the kidneys in glucose homeostasis in type 2 diabetes: Clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors"

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Metabolism

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The role of the kidneys in glucose homeostasis in type 2 diabetes: Clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors

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John P.H. Wilding*

Department of Obesity and Endocrinology, University of Liverpool, United Kingdom

ARTICLE INFO

ABSTRACT

Article history: Received 10 February 2014 Accepted 30 June 2014

Keywords: Kidneys

Type 2 diabetes mellitus Sodium glucose co-transporter 2 (SGLT2) inhibitor

The kidneys play an important role in regulating glucose homeostasis through utilization of glucose, gluconeogenesis, and glucose reabsorption via sodium glucose co-transporters (SGLTs) and glucose transporters. The renal threshold for glucose excretion (RTG) is increased in patients with type 2 diabetes mellitus (T2DM), possibly due to upregulation of SGLT2 and SGLT1 expression. The resulting increase in renal glucose reabsorption is thought to contribute to the maintenance of hyperglycemia in patients with T2DM. Selective SGLT2 inhibitors reduce the RTG, thereby increasing glucosuria, and have demonstrated favorable efficacy and safety in patients with T2DM inadequately controlled with diet and exercise and other glucose-lowering treatments. © 2014 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction

Type 2 diabetes mellitus (T2DM) is a chronic disease that is associated with obesity and the progressive development of hyperglycemia [1]. Increased body fat is associated with the development of insulin resistance in muscle and in the liver, particularly if excess fat is deposited in these tissues (ie, ectopic fat). Initially, the pancreas is able to overcome this insulin resistance by producing more insulin, but in diabetes there is a progressive failure of ß-cell output, resulting first in glucose intolerance and then overt T2DM. In addition to these established factors, it is now known that multiple defects,

involving numerous metabolic pathways and organ systems, contribute to the progression of hyperglycemia in T2DM. These include adipocytes (accelerated lipolysis), the gastrointestinal tract (incretin deficiency/resistance), pancreatic a-cells (hyperglucagonemia), the brain (insulin resistance), and the kidneys (increased glucose reabsorption) [1].

With this further elucidation of the key mechanisms underlying the pathology of T2DM, understanding the role of the kidneys in glucose homeostasis under normal and pathological conditions has increased [2]. This review article explores the role of the kidneys in regulating gluconeogenesis and glucose utilization, and how this is disturbed in T2DM.

Abbreviations: ATPase, adenosine triphosphatase; eGFR, estimated glomerular filtration rate; EGP, endogenous glucose production; FPG, fasting plasma glucose; FRG, familial renal glucosuria; GFR, glomerular filtration rate; GGM, glucose-galactose malabsorption; GLP-1, glucagon-like peptide-1; GLUT, glucose transporter; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; RTG, renal threshold for glucose excretion; SGLT, sodium glucose co-transporter; TmG, tubular maximum glucose reabsorptive capacity; T2DM, type 2 diabetes mellitus; UGE, urinary glucose excretion.

* Department of Obesity and Endocrinology, Institute of Ageing and Chronic Disease, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool, L9 7AL, United Kingdom. Tel.: +44 151 529 5885; fax: +44 151 529 5888.

E-mail address: J.P.H.Wilding@liverpool.ac.uk. http://dx.doi.org/10.1016/j.metabol.2014.06.018

0026-0495/© 2014 The Author. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

2. Renal gluconeogenesis in the postabsorptive state

In the fasting (postabsorptive) state in healthy individuals, the kidneys contribute about 20% to 25% of the glucose released into the circulation via gluconeogenesis (15-55 g per day), with the liver responsible for the remainder via both glycogenolysis and gluconeogenesis [2-4]. Renal gluconeogenesis occurs predominantly within proximal tubule cells in the renal cortex, and is chiefly regulated by insulin and catecholamines (eg, adrenaline). Insulin reduces renal gluconeogenesis directly, and also reduces the availability of gluconeogenic substrates, such as lactate, glutamine, and glycerol [5], thus reducing glucose release into the circulation [4,6,7]. Adrenaline stimulates renal gluconeogenesis [3,8], stimulates renal glucose release, inhibits insulin secretion, increases the supply of gluconeogenic substrates, and reduces renal glucose uptake [2,9].

In patients with T2DM, both renal and hepatic glucose release are increased as a result of increased gluconeogenesis. The relative increase in renal gluconeogenesis is thought to be substantially greater than in hepatic gluconeogenesis (300% vs 30%) [2]. Renal glycogenolysis is minimal in healthy individuals but may play a role in increased renal glucose release in patients with T2DM, due to accumulation of glycogen in diabetic kidneys [5].

3. Renal glucose release in the postprandial state

Renal gluconeogenesis increases during the postprandial state relative to the postabsorptive state. Studies using stable isotopes to estimate renal glucose balance have shown renal glucose release increases more than 2-fold during the 4.5-hour postprandial period [5,10]. It is thought that this increase in renal glucose release allows for repletion of hepatic glycogen stores by permitting suppression of hepatic glucose release. The mechanisms for this are not known, but may include the postprandial increases in lactate and amino acids that are precursors for gluconeogenesis, as well as an increase in sympathetic nervous system activity. Indeed, renal glucose production accounts for ~60% of endogenous glucose release during the postprandial period (4-6 hours after meals) [5,10].

The increase in glucose release over the 4.5-hour postprandial period has been shown to be roughly 30% higher (100 g vs 70 g) in patients with T2DM compared with healthy individuals, primarily due to increased endogenous glucose release. It is estimated that 40% of the increase in endogenous glucose release occurs via the kidney. Renal glucose release is regulated by insulin; thus, as insulin resistance increases, suppression of renal glucose release decreases [2]; an additional explanation may be an increase in renal glucose reabsorption due to upregulation of renal glucose transporters (GLUTs).

reabsorption occurs via both sodium glucose co-transporters (SGLTs) and GLUTs [12,15,16]. The energy for SGLT-mediated active transport of glucose (against its concentration gradient) across the cell membrane is derived from the sodium electrochemical potential gradient (Fig. 1). This is maintained by the transport of intracellular sodium ions into the blood via sodium-potassium adenosine triphosphatase (ATPase) pumps situated in the basolateral membrane [12,15]. GLUTs bind glucose, inducing a conformational change, and glucose is passively transported across the cell membrane from the intracellular compartment into the plasma [16].

Within the proximal renal tubule, 2 key subtypes of SGLT and GLUT are responsible for glucose reabsorption and are expressed at the luminal brush border and the basolateral membrane of the epithelial cells, respectively (Fig. 1) [15,16]. SGLT2 is a high-capacity, low-affinity co-transporter that is responsible for the majority of renal glucose reabsorption, coupling the active transport of sodium and glucose in a 1:1 ratio within the early proximal tubule [11,16,17]. Glucose is then reabsorbed into the circulation via GLUT2 [15]. Any remaining glucose is reabsorbed by SGLT1, a high-affinity

Early portion of the proximal tubule

Glucos

Plasma

№+C>0

Tight junction

Distal proximal tubule

Glucose

Na+/K+ ATPase pump

Lateral intercellular space -I

Glucose

Na+/K+ ATPase pump

4. Renal glucose transport

The kidneys play a key role in glucose conservation, filtering 160 to 180 g of glucose per day in healthy individuals, which is all reabsorbed within the proximal tubules [1,11-14]. Glucose

Fig. 1 - SGLTs and passive GLUTs in the proximal renal tubule [19]. Reprinted from Trends in Pharmacological Sciences, Vol 32 (2), Bailey CJ, Renal glucose reabsorption inhibitors to treat diabetes, pp. 63-71, Copyright (2011), with permission from Elsevier. SGLT, sodium glucose co-transporter; GLUT, glucose transporter; ATPase, adenosine triphosphatase.

transporter expressed within the distal proximal tubule (sodium:glucose ratio of 2:1) and then reabsorbed into the blood via GLUT1 [11,15,17].

5. Renal glucose reabsorption and the renal threshold for glucose excretion

The physiologic relationship between plasma glucose concentration and renal glucose flux (ie, filtration, reabsorption, and excretion) has typically been described as a threshold-type relationship (Fig. 2) [14,18]. The amount of glucose filtered by the kidneys increases in a linear manner with increasing plasma glucose concentration and decreases with declining glomerular filtration rate (GFR); renal glucose reabsorption increases linearly until a certain concentration of plasma glucose is present [2,14,16]. However, there is a distinct deviation (the "splay") from this linear relationship as the renal capacity to reabsorb glucose nears saturation that is thought to be due to variability in the maximal reabsorptive capacity between individual nephrons [14,18].

Under normal conditions in healthy individuals, nearly all filtered glucose is reabsorbed in the renal tubules [17]. However, when the filtered glucose load exceeds the tubular maximum glucose reabsorptive capacity (TmG; approximately 375 mg/min [425 g/day] in healthy individuals), excess glucose is excreted in the urine (Fig. 2) [2,13,17,19]. The renal threshold for glucose excretion (RTG) is the plasma glucose concentration at which TmG is exceeded; below this concentration, glucosuria is minimal [20]. A novel method for measuring RTG in the clinical trial setting, which uses data collected from a mixed-meal tolerance test, has recently been developed and validated [21]. The parameters of blood glucose concentration, urinary glucose excretion (UGE), and estimated

-S £ 400

ob 200 -

GFR (eGFR) are used to calculate RTG when 24-hour UGE is more than 600 mg. This may provide a simple tool for the further investigation of the role of RTG during hyperglycemia.

Increased tubular reabsorption in the context of diabetes has been observed using a rat model of diabetes—RTG levels of approximately 415 mg/dL (23 mmol/L) were seen and gluco-suria was not evident until blood glucose levels were above 400 mg/dL (22 mmol/L) [22]. Consistent with this, RTG is often reported to be approximately 180 to 200 mg/dL (10-11 mmol/L) in healthy individuals [18,23,24]; whereas, in patients with T2DM, RTg is elevated [24-28] (Fig. 3). While studies evaluating RTG in patients with T2DM suggest some interindividual variability, many patients demonstrate elevated values above the normal range, with values ranging from 112 to 240 mg/dL (6.2-13.3 mmol/L) [24-28].

TmG may also be elevated in individuals with diabetes, contributing to the worsening of hyperglycemia [29,30]. Increased tubular reabsorption may be due to an increase in GLUT expression or activity, with upregulation of SGLT2 or GLUT2 being possible mechanisms for the increase in glucose reabsorption. In one study, proximal tubular cells were isolated from the urine of patients with T2DM and healthy controls [31]. In a hyperglycemic culture environment, both SGLT2 and GLUT2 mRNA levels and glucose transport were significantly higher in the T2DM group versus controls. Rodent models of diabetes have produced similar results, reporting that expression of renal SGLT2, GLUT2, and SGLT1 was significantly increased compared with normal controls [32-34].

The increases in tubular reabsorption in individuals with T2DM lead to an increase in glucose flux into the blood, resulting in an exacerbation of hyperglycemia [1,14,16]. Based on observations that mean RTG is approximately 40 mg/dL (2.2 mmol/L) higher in patients with T2DM [24-28] than the commonly reported values of 180 to 200 mg/dL (10-11 mmol/L) in healthy individuals [18,23,24], and using a mean GFR of 100 mL/min, calculations suggest that elevated RTG leads to an average of approximately 50 to 70 mg/min of additional glucose reabsorbed into the circulation when plasma glucose is above the RTG, relative to glucose reabsorption if RTG was not increased. For comparison, elevated hepatic glucose production is estimated to contribute approximately 24 mg/min of additional glucose in a 100-kg patient with T2DM (assuming a 12% increase from a baseline value of 2 mg/kg/min) [35]. Thus, both the kidney and the liver substantially contribute to the hyperglycemia seen in patients with T2DM. However, it should be noted that additional renal glucose reabsorption may be substantially lower in patients with impaired renal function, since their GFR will be lower than 100 mL/min.

Plasma glucose (mmol/L)

Fig. 2 - The relationship between plasma glucose concentration and renal glucose reabsorption in normoglycemic individuals [16]. Reprinted from Current Medical Research and Opinion, Vol 25 (3), Bays H, From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus, pp. 671-681, Copyright (2009), with permission from Informa Healthcare. TmG, tubular maximum glucose reabsorptive capacity; RTG, renal threshold for glucose excretion.

6. Genetic defects in renal glucose transport

Specific mutations in SGLT genes can result in naturally occurring glucosuria. Glucose-galactose malabsorption (GGM) is a rare condition caused by mutations of SGLT1, leading to malabsorption of these sugars due to failure of the gastrointestinal epithelial cells to accumulate sugar across the brush border membrane [12,36]. This results in gastrointestinal symptoms

Below RTg minimal glucosuria occurs

Plasma glucose (mmol/L)

Fig. 3 - Linear relationship between UGE and plasma glucose concentration in healthy individuals and patients with T2DM. aUGE, urinary glucose excretion; T2DM, type 2 diabetes mellitus; RTG, renal threshold for glucose excretion. aThe actual relationship between plasma glucose concentration and UGE contains some splay in the region near RTG [81]; an idealized relationship is depicted here.

such as diarrhea and dehydration presenting in the neonatal period [36]; treatment requires removal of glucose and galactose (which is also transported by SGLT1) from the diet. Glucosuria in individuals with GGM is typically absent or mild, consistent with the minor role of SGLT1 in renal glucose reabsorption [12,36].

Familial renal glucosuria (FRG) is a rare autosomal recessive renal disorder that results from mutations in the SLC5A2 gene (coding for SGLT2) in the majority of cases [37,38]. Heterozygous FRG is characterized by glucosuria of ~0 to 10 g/day at normal plasma glucose concentrations in the absence of renal tubular dysfunction [17,39]. FRG is generally asymptomatic and considered to be a benign condition [12,17,39]. Homozygous FRG may result in glucosuria of up to 200 g/day [14,37,38], but is rarely described. However, available data from families with homo-zygous FRG indicate that these individuals are asymptomatic, with no history of polyuria, polydipsia, renal disease, or increased frequency of urinary tract infections [14,37,38].

7. SGLT2 inhibition for the treatment of T2DM

Inhibition of SGLT2 has emerged as a focus for the development of novel treatments for patients with T2DM [14,19]. These therapies reduce blood glucose concentrations by lowering the RTG and inducing glucosuria in an insulin-independent manner [2,18,19]. Two SGLT2 inhibitors, canagli-flozin and dapagliflozin, are currently approved for use in patients with T2DM in over 30 countries worldwide, including the United States and the European Union, and other drugs are currently in clinical development [40-45]. Table 1 summarizes the approved indications for canagliflozin and dapagliflozin [41,42,46,47].

Canagliflozin is an orally active inhibitor of SGLT2 that lowers elevated plasma glucose concentrations by reducing reabsorption of filtered glucose in patients with T2DM [28]. Canagliflozin's affinity for SGLT2 is approximately 150-fold greater than its affinity for SGLT1 [22]. Treatment with canagliflozin has been shown to decrease 24-hour mean RTG in a dose-dependent manner, with maximal suppression (at doses >100 mg once daily) to approximately 60 mg/dL (3.3 mmol/L) in healthy individuals [18,24] and to approxi-

mately 70 to 90 mg/dL (3.9-5.0 mmol/L) in patients with T2DM [48-50]. Analysis of data from four Phase 1 pharmacodynamic studies of canagliflozin has shown that RTG is consistently correlated with 24-hour mean plasma glucose concentration in patients with T2DM (Fig. 4) [48,49,51]. The 300-mg dose of canagliflozin has been shown to provide a greater reduction in postprandial plasma glucose excursion than that observed with the 100-mg dose [49]. This effect may be due, in part, to local inhibition of intestinal SGLT1 (an important intestinal GLUT) related to transient high concentrations of canagli-flozin in the intestinal lumen prior to medicinal product absorption [20,52] (canagliflozin is a low potency inhibitor of SGLT1 [22,53]). However, systemic levels of canagliflozin 300 mg did not meaningfully inhibit SGLT1 and studies have shown no glucose malabsorption with canagliflozin [20].

Results from placebo- and active-controlled Phase 3 studies of canagliflozin are summarized in Table 2. As monotherapy or as adjunctive treatment to existing oral antidiabetic drugs, canagliflozin has been shown to significantly reduce HbA1c and fasting plasma glucose (FPG) compared with placebo [54-61]. The increased UGE with SGLT2 inhibition also translates to osmotic diuresis, with the diuretic effect leading to reductions in systolic blood pressure compared with placebo. The increase in UGE also results in a net loss of calories and, therefore, a sustained reduction in body weight, as has been demonstrated in clinical trials of up to 2 years in duration conducted in patients with T2DM [54-61].

Dapagliflozin is an orally active SGLT2 inhibitor with selectivity for SGLT2 that is more than 1400-fold greater relative to SGLT1 [42]. Treatment with dapagliflozin has been shown to lower RTG and induce UGE, resulting in significantly decreased plasma glucose concentrations in healthy individuals [62] and in patients with T2DM [63]. In randomized, placebo- and active-controlled trials, dapagliflozin provided statistically significant improvements in terms of HbA1c and FPG (Table 2) [64-67]; body weight and systolic blood pressure reductions were non-glycemic benefits observed in these studies [64-66,68].

Canagliflozin and dapagliflozin are generally well tolerated in patients with T2DM (Table 2) [54-59,64-67]. The associated increase in UGE that contributes to reductions in

Table 1 - Approved Indications for Canagliflozin and Dapagliflozin [41,42,46,47].

Generic Trade Approved indications Dosing Studied Restrictions

name name combinations

Canagliflozin Invokana® • Recommended starting Monotherapy • Canagliflozin should

(EU) Indicated in adults aged 18 years or dose is 100 mg QD +MET not be initiated in

older with T2DM to improve glycemic • Dose can be increased to + SU patients with eGFR

control as monotherapy when diet 300 mg QD for patients +MET and SU <60 mL/min/1.73 m2 or

and exercise do not provide adequate with eGFR >60 mL/min/ +MET and PIO with CrCl <60 mL/min

glycemic control and use of MET is 1.73 m2 who require +Insulin ± • Canagliflozin 100 mg can

inappropriate; and as add-on therapy additional glycemic other AHAs be used in patients with

with other AHAs, including insulin, control eGFR between 45

when these, together with diet and and 60 mL/min/1.73 m2

exercise, do not provide adequate • Not for use in patients

glycemic control with eGFR persistently

<45 mL/min/1.73 m2

• Not for treatment of

T1DM or diabetic

ketoacidosis

Invokana® • Recommended starting • Canagliflozin 100 mg can

(US) Adjunct to diet and exercise to dose is 100 mg QD be used in patients with

improve glycemic control in • Dose can be increased to eGFR between 45 and

adults with T2DM 300 mg QD for patients 60 mL/min/1.73 m2

with eGFR >60 mL/min/ • Not for use in patients with

1.73 m2 who require eGFR persistently

additional glycemic <45 mL/min/1.73 m2

control • Not for treatment of

T1DM or diabetic

ketoacidosis

Dapagliflozin Forxiga® For patients with T2DM to improve • Recommended dose is Monotherapy • Not recommended for

(EU) glycemic control as monotherapy 10 mg QD +MET patients with CrCl

when diet and exercise do not provide • A starting dose of 5 mg QD + SU <60 mL/min or eGFR

adequate glycemic control and use of can be used for patients +MET and SU <60 mL/min/1.73 m2

MET is inappropriate; or in with severe hepatic + SITA ± MET • Not for treatment of

combination with other AHAs, impairment +Insulin ± T1DM or diabetic

including insulin, when these, other AHAs ketoacidosis

together with diet and exercise, do not

provide adequate glycemic control

Farxiga™ Adjunct to diet and exercise to • Recommended starting • Not recommended for

(US) improve glycemic control in adults dose is 5 mg QD patients with CrCl

with T2DM • Dose can be increased to <60 mL/min or eGFR

10 mg QD for patients who <60 mL/min/1.73 m2

require additional • Not for treatment of

glycemic control T1DM or diabetic

ketoacidosis

T2DM, type 2 diabetes mellitus; MET, metformin; AHA, antihyperglycemic agent; QD, once daily; eGFR, estimated glomerular filtration rate; SU,

sulfonylurea; PIO, pioglitazone; CrCl, creatinine clearance; SITA, sitagliptin; T1DM, type 1 diabetes mellitus.

plasma glucose, body weight, and blood pressure may also be related to adverse events seen with SGLT2 inhibition, including genital mycotic infections, urinary tract infections, and adverse events related to osmotic diuresis (eg, pollakiuria [increased urine frequency], polyuria [increased urine volume]) and volume depletion (eg, postural dizziness, orthostatic hypotension) [41,42,69-72]. SGLT2 inhibition has been associated with modest, transient decreases in eGFR ranging from roughly 3% to 10% that attenuated with continued treatment and are consistent with volume loss associated with the osmotic diuresis [55,59,73]. Low incidences of hypoglycemia have been reported with canagliflozin and dapagliflozin when not

used together with insulin or insulin secretagogues, such as sulfonylureas [55,57,59,64,74]. This low risk of hypoglycemia is anticipated due to a mechanism of action whereby RTG is lowered to a level above the usual threshold for hypoglycemia; the increased hepatic glucose production may also help protect against hypoglycemia [75,76]. As might be expected, rates of hypoglycemia with the SGLT2 inhibitors compared favorably with those observed for sulfonylureas in head-to-head studies [55,68,77].

Across clinical studies, canagliflozin was generally associated with decreases in triglycerides and increases in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) [41]. Dapagliflozin has been

• Study 1 ■ Study 2 * Study 3 ♦ Study 4 - Regression3

24-h mean plasma glucose (mmol/L)

Fig. 4 - Relationship between RTG and 24-hour mean plasma glucose concentration in patients with T2DM: data from 4 clinical studies of canagliflozin [48,49,51]. RTG, renal threshold for glucose excretion; T2DM, type 2 diabetes mellitus. ar2 = 0.4.

associated with increased HDL-C, LDL-C, and total cholesterol [42]. The mechanism accounting for increases in LDL-C observed with SGLT2 inhibitors is currently unknown, but may be related to metabolic changes associated with increased UGE. Changes in laboratory parameters seen with canagliflozin and dapagliflozin included modest decreases in liver transaminases and serum urate, and modest increases in blood urea nitrogen, hemoglobin, and hematocrit [41,42].

Interestingly, 2 recent studies [75,76] have shown that SGLT2 inhibition decreases plasma insulin secretion and increases plasma glucagon levels. Endogenous glucose production (EGP) is increased, most likely as a result of increased hepatic glucose production in response to elevated glucagon levels. This increase in EGP attenuates the reduction in fasting glucose levels, such that normoglycemia is achieved (eg, in patients with T2DM treated with the SGLT2 inhibitor empagliflozin, it was calculated that, withoutthe increase in EGP, average fasting glycemia would have been 4.7 mmol/L instead of the achieved value of 6.7 mmol/L) [75]. Improvements in insulin sensitivity and p-cell function observed with SGLT2 inhibition are likely a result of reversal of the glucotoxicity caused by chronic hyperglycemia. They also provide confirmation of the concept of reciprocal links between renal and hepatic glucose metabolism [5]. The novel and unexpected finding of increased glucagon during SGLT2 inhibition may well explain the compensatory increase in hepatic glucose production and does raise the possibility that drugs that suppress glucagon, such as glucagon-like peptide-1 (GLP-1) analogues, may provide synergistic therapeutic effects. The observation of increased fat oxidation is also of interest, providing a mechanistic explanation for the decreases in body fat seen during SGLT2 inhibitor treatment [78]. Overall, these mechanistic studies support clinical findings that SGLT2 inhibition reduces fasting and

postprandial glucose, both acutely and chronically, with a low risk for hypoglycemia [75,76].

8. SGLT2 inhibition in T1DM

Results from pilot studies of dapagliflozin [79] and empagli-flozin [80] suggest that SGLT2 inhibition may also provide clinical benefits as an adjunct to insulin in patients with T1DM. In these studies, SGLT2 inhibition was associated with improvements in glycemic control, reductions in daily insulin doses, and reductions in body weight. Further study of the therapeutic potential of SGLT2 inhibitors as add-on therapy to insulin in patients with T1DM is warranted.

9. Conclusions

The kidneys play an important role in regulating glucose homeostasis through gluconeogenesis, glucose uptake and utilization, and glucose reabsorption in the proximal renal tubule. The RTG is the plasma glucose concentration at which glucose reabsorption capacity is exceeded and glucosuria occurs. The RTG has been estimated to be between 180 and 200 mg/dL (10-11 mmol/L) in healthy individuals; this is increased in patients with T2DM. The resulting increase in glucose reabsorption is thought to contribute to the maintenance of hyperglycemia. The inhibition of renal glucose reabsorption and induction of glucosuria with SGLT2 inhibitors has demonstrated favorable efficacy and safety in patients with T2DM inadequately controlled with diet and exercise and other glucose-lowering drugs; advantages and disadvantages of using SGLT2 inhibitors for the treatment of T2DM are summarized in Table 3.

As the prevalence of T2DM grows, selecting appropriate antihyperglycemic agents to manage T2DM will continue to challenge healthcare providers. Overall, it is likely that SGLT2 inhibitors will prove to be valuable new antihyperglycemic agents for the treatment of patients with T2DM. This review provides valuable information on the mechanism of action and the efficacy and safety of SGLT2 inhibitors for clinicians who are considering the implementation of these agents in the therapeutic regimens of their patients.

Acknowledgments

Editorial support was provided by Cherie Koch, PhD, of MedErgy, and was funded by Janssen Pharmaceutica NV. The author retained full editorial control over the content of the article.

Conflict of interest statement

J.P.H.W. has received research funding from Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novo Nordisk, Merck Sharpe & Dohme, Janssen/Johnson & Johnson, and

Table 2 - Summary of Results From Placebo- and Active-Controlled Studies of Canagliflozin and Dapagliflozin

[55-57,59,60,64,65,77].

Placebo-controlled studies (26 weeks for CANA and 24 weeks for DAPA)

Mean change from baseline vs placebo

Drug HbAlc (%) FPG (mmol/L) Body weight (kg) SBP (mmHg) Summary of safety across

placebo-controlled studies

CANA 100 mg • Generally well tolerated

Monotherapy • Higher incidence of genital my-

Baseline 8.1 vs 8.0 9.6 vs 9.2 85.9 vs 87.5 126.7 vs 127.7 cotic infections, UTIs, and osmotic

Change -0.77 vs 0.14 -1.5 vs 0.5 -2.5 vs -0.5 -3.3 vs 0.4 diuresis-related AEs vs placebo

Add-on to MET • Incidence of hypoglycemia

Baseline 7.9 vs 8.0 9.4 vs 9.1 88.7 vs 86.7 128.0 vs 128.0 similar to placebo

Change -0.79 vs -0.17 -1.5 vs 0.1 -3.3 vs -1.1 -3.8 vs 1.5

Add-on to MET + SU

Baseline 8.1 vs 8.1 9.6 vs 9.4 93.5 vs 90.8 130.4 vs 130.1

Change - 0.85 vs - 0.13 -1.0 vs 0.2 -1.9 vs -0.8 -4.9 vs -2.7

CANA 300 mg

Monotherapy

Baseline 8.0 vs 8.0 9.6 vs 9.2 86.9 vs 87.5 128.5 vs 127.7

Change -1.03 vs 0.14 -1.9 vs 0.5 -3.4 vs -0.5 -5.0 vs 0.4

Add-on to MET

Baseline 8.0 vs 8.0 9.6 vs 9.1 85.4 vs 86.7 128.7 vs 128.0

Change - 0.94 vs - 0.17 -2.1 vs 0.1 -3.6 vs -1.1 -5.1 vs 1.5

Add-on to MET + SU

Baseline 8.1 vs 8.1 9.3 vs 9.4 93.5 vs 90.8 130.8 vs 130.1

Change -1.06 vs - 0.13 -1.7 vs 0.2 -2.5 vs -0.8 -4.3 vs -2.7

DAPA 5 mg • Generally well tolerated

Monotherapy • Higher incidence of genital

Baseline 7.9 vs 7.8 9.0 vs 8.9 87.6 vs 88.8 NR mycotic infections, UTIs, and

Change -0.77 vs -0.23 -1.3 vs - 0.2 -2.8 vs -2.2 -2.3 vs -0.9 osmotic diuresis-related AEs vs

Add-on to MET placebo

Baseline 8.2 vs 8.1 9.4 vs 9.2 84.7 vs 87.7 126.9 vs 127.7 • Incidence of hypoglycemia is

Change -0.70 vs -0.30 -1.2 vs -0.3 - 3.0 vs - 0.9 -4.3 vs -0.2 similar to placebo

DAPA 10 mg

Monotherapy

Baseline 8.0 vs 7.8 9.2 vs 8.9 94.2 vs 88.8 NR

Change -0.89 vs -0.23 -1.6 vs -0.2 -3.2 vs -2.2 -3.6 vs -0.9

Add-on to MET

Baseline 7.9 vs 8.1 8.7 vs 9.2 86.3 vs 87.7 126.0 vs 127.7

Change -0.84 vs -0.30 -1.3 vs -0.3 - 2.9 vs - 0.9 -5.1 vs -0.2

Active-controlled studies (52 weeks)

Mean change from baseline vs comparator

Drug HbAic (%) FPG (mmol/L) Body weight (kg) SBP (mmHg) Summary of safety across active-

controlled studies

CANA 100 mg • Higher incidence of genital

Add-on to MET vs GLIM mycotic infections vs GLIM and

Baseline 7.8 vs 7.8 9.2 vs 9.2 86.8 vs 86.6 130.0 vs 129.5 SITA

Change -0.82 vs -0.81 -1.4 vs -1.0 -3.7 vs 0.7 -3.3 vs 0.2 • Higher incidence of UTIs vs

Add-on to MET vs SITA GLIM; similar incidence vs SITA

Baseline 7.9 vs 7.9 9.4 vs 9.4 88.7 vs 87.6 128.0 vs 128.0 • Higher incidence of osmotic

Change -0.73 vs -0.73 -1.5 vs -1.0 -3.3 vs -1.2 -3.5 vs -0.7 diuresis-related AEs vs SITA

CANA 300 mg • Incidence of hypoglycemia

Add-on to MET vs GLIM similar to SITA; significantly

Baseline 7.8 vs 7.8 9.1 vs 9.2 86.6 vs 86.6 130.0 vs 129.5 lower vs GLIM

Change -0.93 vs -0.81 -1.5 vs -1.0 -4.6 vs 0.7 -4.6 vs 0.2

Add-on to MET vs SITA

Baseline 8.0 vs 7.9 9.6 vs 9.4 85.4 vs 87.6 128.7 vs 128.0

Change -0.88 vs -0.73 -2.0 vs -1.0 -3.7 vs -1.2 -4.7 vs -0.7

Add-on to MET + SU vs SITA

Baseline 8.1 vs 8.1 9.4 vs 9.1 87.6 vs 89.6 131.2 vs 130.1

Change -1.03 vs -0.66 -1.7 vs -0.3 -2.3 vs 0.1 -5.1 vs 0.9

Table 2 (continued)

Active-controlled studies (52 weeks)

Mean change from baseline vs comparator

Drug HbA1c (%) FPG (mmol/L) Body weight (kg) SBP (mmHg) Summary of safety across active-controlled studies

DAPAa Add-on to MET vs GLIP Baseline 7.7 vs 7.7 Change -0.S2 vs -0.S2 9.0 vs 9.1 -1.2 vs -1.0 88.4 vs 87.6 -3.2 vs 1.4 132.8 vs 133.8 -4.3 vs 0.8 • Higher incidence of genital mycotic infections and UTIs vs GLIP • Incidence of hypoglycemia significantly lower vs GLIP

CANA, canagliflozin; DAPA, dapagliflozin; FPG, fasting plasma glucose; SU, sulfonylurea; SBP, systolic blood pressure; UTI, urinary tract infection; AE, adverse event; MET, metformin; NR, not reported; GLIM, glimepiride; SITA, sitagliptin; GLIP, glipizide.

a Patients received starting doses of DAPA 2.5 mg or GLIP 5 mg, and the dose could be titrated if FPG was > 110 mg/dL. Maximum doses were 10 mg for DAPA and 20 mg for GLIP; mean doses at the end of the study were 9.2 mg for DAPA and 16.4 mg for GLIP.

Table 3 - Advantages and Disadvantages of Using SGLT2 Inhibitors to Improve Glycemic Control in Patients With T2DM.

Advantages Disadvantages

• Significant improvements in glycemic control sustained over time • Sustained, clinically meaningful reductions in body weight • Sustained, clinically meaningful reductions in systolic blood pressure • Insulin-independent mechanism of action • Improvements in insulin sensitivity and p-cell function • Generally safe and well tolerated • Low risk of hypoglycemia • Can be used as monotherapy or combined with other AHAs, including insulin • Increased incidence of mild to moderate genital mycotic infections and UTIs vs comparators • Higher incidence of osmotic diuresis-related AEs vs comparators • Increased incidence of volume depletion-related AEs in elderly patients and in patients with eGFR <60 mL/min/1.73 m2 • Increased LDL-C levels

SGLT2, sodium glucose co-transporter 2; T2DM, type 2 diabetes mellitus; AHA, antihyperglycemic agent; UTI, urinary tract infection; AE, adverse event; eGFR, estimated glomerular filtration rate; LDL-C, low-density lipoprotein cholesterol.

Sanofi, and has provided consulting and/or lectures for Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen/Johnson & Johnson, Lilly, Merck Sharpe & Dohme, and Novo Nordisk.

REFERENCES

[1] Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-95.

[2] Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med 2010;27:136-42.

[3] Stumvoll M, Chintalapudi U, Perriello G, et al. Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine. J Clin Invest 1995;96:2528-33.

[4] Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab 2000;2:345-50.

[5] Gerich JE, Meyer C, Woerle HJ, et al. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 2001;24:382-91.

[6] Cersosimo E, Garlick P, Ferretti J. Insulin regulation of renal glucose metabolism in humans. Am J Physiol 1999;276:E78-84.

[7] Meyer C, Dostou J, Nadkarni V, et al. Effects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism. Am J Physiol 1998;275:F915-21.

[8] Meyer C, Stumvoll M, Welle S, et al. Relative importance of liver, kidney, and substrates in epinephrine-induced increased gluconeogenesis in humans. Am J Physiol Endocrinol Metab 2003;285:E819-26.

[9] Shrayyef MZ, Gerich JE. Normal glucose homeostasis. In: Poretsky L, editor. Principles of Diabetes Mellitus. New York, NY: Springer; 2010. p. 19-35.

[10] Meyer C, Dostou JM, Welle SL, et al. Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am J Physiol Endocrinol Metab 2002;282:E419-27.

[11] Wright EM. Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol 2001;280:F10-8.

[12] Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med 2007;261:32-43.

[13] Bakris GL, Fonseca VA, Sharma K, et al. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int 2009;75:1272-7.

[14] Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev 2011;32:515-31.

[15] Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 2003; 89:3-9.

[16] Bays H. From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus. Curr Med Res Opin 2009;25:671-81.

[17] Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev 2011;91:733-94.

[18] Nair S, Wilding JP. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab 2010;95:34-42.

[19] Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci 2011;32:63-71.

[20] Polidori D, Sha S, Mudaliar S, et al. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care 2013;36:2154-61.

[21] Polidori D, Sha S, Ghosh A, et al. Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 2013;98:E867-71.

[22] Liang Y, Arakawa K, Ueta K, et al. Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models. PLoS One 2012;7:e30555.

[23] Guyton A, Hall J. Textbook of Medical Physiology. Philadelphia, PA: Elsevier Saunders; 2006.

[24] Rave K, Nosek L, Posner J, et al. Renal glucose excretion as a function of blood glucose concentration in subjects with type 2 diabetes—results of a hyperglycaemic glucose clamp study. Nephrol Dial Transplant 2006;21:2166-71.

[25] Ruhnau B, Faber OK, Borch-Johnsen K, et al. Renal threshold for glucose in non-insulin-dependent diabetic patients. Diabetes Res Clin Pract 1997;36:27-33.

[26] Wolf S, Rave K, Heinemann L, et al. Renal glucose excretion and tubular reabsorption rate related to blood glucose in subjects with type 2 diabetes with a critical reappraisal of the "renal glucose threshold" model. Horm Metab Res 2009;41:600-4.

[27] Polidori D, Sha S, Sarich T, et al. Canagliflozin lowers the renal threshold for glucose excretion in lean, obese and type 2 diabetic subjects [abstract]. Diabetologia 2010;53:S350.

[28] Devineni D, Morrow L, Hompesch M, et al. Canagliflozin improves glycemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab 2012;14:539-45.

[29] Farber SJ, Berger EY, Earle DP. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J Clin Invest 1951;30:125-9.

[30] Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand J Clin Lab Invest 1971;28:101-9.

[31] Rahmoune H, Thompson PW, Ward JM, et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005;54:3427-34.

[32] Vestri S, Okamoto MM, de Freitas HS, et al. Changes in sodium or glucose filtration rate modulate expression of glucose transporters in renal proximal tubular cells of rat. J Membr Biol 2001;182:105-12.

[33] Freitas HS, Anhe GF, Melo KF, et al. Na(+)-glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology 2008;149:717-24.

[34] Tabatabai NM, Sharma M, Blumenthal SS, et al. Enhanced expressions of sodium-glucose cotransporters in the kidneys of diabetic Zucker rats. Diabetes Res Clin Pract 2009;83:e27-30.

[35] Beck-Nielsen H, Hother-Nielsen O, Staehr P. Is hepatic glucose production increased in type 2 diabetes mellitus? Curr Diab Rep 2002;2:231-6.

[36] Turk E, Zabel B, Mundlos S, et al. Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nature 1991;350:354-6.

[37] Calado J, Sznajer Y, Metzger D, et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and

further evidence of volume depletion. Nephrol Dial Transplant 2008;23:3874-9.

[38] Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol 2003;14:2873-82.

[39] Santer R, Calado J. Familial renal glucosuria and SGLT2: from a Mendelian trait to a therapeutic target. Clin J Am Soc Nephrol 2010;5:133-41.

[40] Zambrowicz B, Freiman J, Brown PM, et al. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther 2012;92:158-69.

[41] INVOKANA™ (canagliflozin) tablets, for oral use [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013.

[42] Summary of Product Characteristics. Forxiga 5 mg and 10 mg film-coated tablets. Middlesex, United Kingdom: Bristol-Myers Squibb/AstraZeneca EEIG; 2012.

[43] Kurosaki E, Ogasawara H. Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: Preclinical and clinical data. Pharmacol Ther 2013;139:51-9.

[44] Miao Z, Nucci G, Amin N, et al. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab Dispos 2013;41:445-56.

[45] Ferrannini E, Seman L, Seewaldt-Becker E, et al. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab 2013;15:721-8.

[46] FARXIGA™ (dapagliflozin) tablets, for oral use [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2014.

[47] INVOKANA™ (canagliflozin) tablets, for oral use [Summary of Product Characteristics]. Beerse, Belgium: Janssen-Cilag International NV; 2013.

[48] Devineni D, Curtin CR, Polidori D, et al. Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. J Clin Pharmacol 2013;53:601-10.

[49] Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab 2011;13:669-72.

[50] Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012;35:1232-8.

[51] Polidori D, Sha S, Liang Y, et al. Renal glucose reabsorption in type 2 diabetes mellitus: new insights from studies with canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor. Poster presented at: the World Diabetes Congress of the International Diabetes Federation; December 4-8, 2011; Dubai, United Arab Emirates.

[52] Stein P, BergJK, Morrow L, et al. Canagliflozin (CANA), a sodium glucose co-transporter 2 (SGLT2) inhibitor, reduces post-meal glucose excursion in patients with type 2 diabetes mellitus (T2DM) by a non-renal mechanism [abstract]. Diabetes 2012;61.

[53] Nomura S, Sakamaki S, Hongu M, et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem 2010;53:6355-60.

[54] Bode B, Stenlof K, Sullivan D, et al. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract 2013;41:72-84.

[55] Cefalu WT, Leiter LA, Yoon K-H, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU):

52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50.

[56] Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week, randomized trial. Diabetes Care 2013;36:2508-15.

[57] Stenlöf K, Cefalu WT, Kim K-A, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013;15:372-82.

[58] Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013;15:463-73.

[59] Lavalle-Gonzâlez FJ, Januszewicz A, Davidson J, et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 2013;56:2582-92.

[60] Wilding JP, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract 2013;67:1267-82.

[61] Cefalu WT, Leiter LA, Yoon K-H, et al. Canagliflozin (CANA) demonstrates durable glycemic improvements over

104 weeks versus glimepiride (GLIM) in subjects with type 2 diabetes mellitus (T2DM) on metformin (MET) [abstract]. Diabetes 2013;62:LB18.

[62] Komoroski B, Vachharajani N, Boulton D, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther 2009;85:520-6.

[63] Komoroski B, Vachharajani N, Feng Y, et al. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther 2009;85:513-9.

[64] Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2010;33:2217-24.

[65] Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.

[66] Strojek K, Yoon KH, Hruba V, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011;13:928-38.

[67] Rosenstock J, Vico M, Wei L, et al. Effects of dapagliflozin, a sodium-glucose cotransporter-2 inhibitor, on hemoglobin A1c, body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 2012;35:1473-8.

[68] Del Prato S, Nauck MA, Duran-Garcia S, et al. Durability of dapagliflozin vs. glipizide as add-on therapies in T2DM inadequately controlled on metformin: 4-year data [abstract]. Diabetes 2013;62:LB17.

[69] Nicolle LE, Capuano G, Fung A, et al. Urinary tract infection in randomized Phase III studies of canagliflozin, a sodium glucose co-transporter 2 inhibitor. Postgrad Med 2014;126:7-17.

[70] Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013;27:473-8.

[71] Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013;27:479-84.

[72] Nyirjesy P, Sobel JD, Fung A, et al. Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr Med Res Opin 2014;30:1109-19.

[73] Ptaszynska A, Chalamandaris A-G, Sugg JE, et al. Effect of dapagliflozin on renal function [abstract]. Diabetes 2012;61:1098-P.

[74] Bailey CJ, Gross JL, Hennicken D, et al. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med 2013;11:43.

[75] Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499-508.

[76] Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014;124:509-14.

[77] Nauck MA, Del PS, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011;34:2015-22.

[78] Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

J Clin Endocrinol Metab 2012;97:1020-31.

[79] Henry RR, Rosenstock J, Chalamandaris A-G, et al. Exploring the potential of dapagliflozin in type 1 diabetes: phase 2a pilot study [abstract]. Diabetes 2013;62:LB20.

[80] Perkins BA, Cherney DZ, Partridge H, et al. Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial. Diabetes Care 2014;37:1480-3.

[81] Defronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 2013;36:3169-76.