Canagliflozin, a sodium glucose co-transporter 2 inhibitor, for the management of type 2 diabetes.

C L I N I C A L F E AT U R E S

Canagliflozin, a Sodium Glucose Co-Transporter 2 Inhibitor, for the Management of Type 2 Diabetes

Hospital Practice Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.

DOI: 10.3810/hp.2014.08.1122

Stephen Brunton, MD 1 Timothy S. Reid, MD 2 Executive Director, Primary Care Metabolic Group, Charlotte, NC; 2 Mercy Diabetes Centers, Janesville, WI 1

Abstract: The kidney plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes mellitus (T2DM). Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of antihyperglycemic agents for the treatment of T2DM with a novel insulinindependent mechanism of action that targets the kidney. The SGLT2 inhibitors decrease renal glucose reabsorption, thereby increasing urinary glucose excretion and lowering plasma glucose levels in patients with hyperglycemia. SGLT2 inhibitor canagliflozin has demonstrated efficacy in improving glycemic control and reducing body weight and blood pressure as monotherapy or as add-on to other antihyperglycemic agents across a broad range of patients with T2DM. Canagliflozin is generally well tolerated, with increased incidences of specific adverse events that are related to the mechanism of SGLT2 inhibition. Findings suggest that canagliflozin is a useful treatment option for patients with T2DM. Keywords: type 2 diabetes mellitus; sodium glucose co-transporter 2 (SGLT2) inhibitor; canagliflozin; kidney; antihyperglycemic agent

Introduction

Correspondence: Stephen Brunton, MD, Primary Care Metabolic Group, 229 Boyce Road, Charlotte, NC 28211. Tel: 704-752-0257 Fax: 704-752-9441 E-mail: [email protected]

96

Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of antihyperglycemic agents (AHAs) developed for the treatment of patients with type 2 diabetes mellitus (T2DM).1–3 Many current classes of AHAs function by promoting insulin production or increasing insulin sensitivity.4 The SGLT2 inhibitors work differently; they lower plasma glucose in individuals with hyperglycemia via a novel, insulin-independent mechanism of action that targets the kidney.1–3 The SGLT2 inhibitors decrease renal glucose reabsorption, thereby increasing urinary glucose excretion (UGE) and lowering plasma glucose levels.1–3 The SGLT2 inhibitors do not interfere with the renal filtration of glucose at the glomerulus. Thus, with SGLT2 inhibitor treatment, the glucosuria that has traditionally been an indicator of metabolic dysfunction is a mechanism that can be leveraged to reduce hyperglycemia. Currently, 2 SGLT2 inhibitors, canagliflozin (INVOKANA, Janssen Pharmaceuticals, Inc, Titusville, NJ)5 and dapagliflozin (FARXIGA, Bristol-Myers Squibb Company, Princeton, NJ),6 are approved in the United States for the treatment of adults with T2DM. Other members of this class are at various stages of clinical development.7–9 This review article focuses on canagliflozin and has the following objectives: (1) to provide an overview of renal physiology, focusing on the role of the kidney in glucose homeostasis and the pathophysiology of T2DM; (2) to describe the mechanism of action of SGLT2 inhibitors; and (3) to summarize efficacy and safety findings from

© Hospital Practice, Volume 42, Issue 3, August 2014, ISSN – 2154-8331 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Canagliflozin for T2DM

clinical studies of canagliflozin.


Role of the Kidney in Glucose Homeostasis and the Pathophysiology of T2DM

The kidney plays an important role in glucose homeostasis, centered around its functions in glucose filtration, glucose reabsorption, and renal gluconeogenesis.10,11 Glucose reabsorption in the kidney is primarily mediated by SGLT2, a high-capacity, low-affinity transporter expressed in the early portion of the proximal renal tubule (Figure 1).12,13 Sodium glucose co-transporter 1 (SGLT1) is a low-capacity, high-affinity transporter expressed in the distal segment of the proximal tubule, which is also involved in renal glucose reabsorption, but to a much lesser extent than SGLT2.14 Under normal circumstances, most of the filtered glucose (∼180 g per day) is reabsorbed by the kidneys, with only a small amount (, 1%) excreted in the urine.1,2 In individuals with hyperglycemia, such as patients with T2DM, the amount of filtered glucose may exceed the renal glucose resorptive capacity, saturating the SGLT receptors and resulting in the excretion of excess glucose in the urine.1,2 The plasma glucose concentration at which UGE occurs is referred to as the renal threshold for glucose excretion (RTG). In healthy individuals, the RTG is reported to be in the range of 180 to 200 mg/dL.15–17 Patients with T2DM have been shown to have an

increased renal capacity for glucose reabsorption compared with healthy individuals (Figure 2).17–20 In patients with T2DM, elevated RTG values of up to 240 mg/dL have been reported.17–20 This paradoxical increase is now recognized as a core pathophysiologic defect of T2DM and is thought to be due to increased expression of glucose transporters, including SGLT2.21 Increased renal capacity results in a greater amount of glucose being reabsorbed into the bloodstream, thereby maintaining or exacerbating hyperglycemia.2,11 Thus, the kidney, as well as SGLT2, plays a key role in the pathophysiology of T2DM.22

Naturally Occurring Examples of SGLT2 Inhibition

Evidence for the efficacy and safety of targeting SGLT2 to manage hyperglycemia in patients with T2DM has been derived from studies of the naturally derived compound phlorizin and from genetic examples of patients with familial renal glucosuria. Inhibition of SGLT2 by a small molecule was first observed with phlorizin, a naturally occurring compound, in studies during the 1950s and 1960s. Although it promotes renal glucose excretion and lowers plasma glucose in diabetic animals, phlorizin has not been commercially developed as a treatment for diabetes due to its lack of bioavailability and poor specificity for SGLT2.2,3 Studies of patients with familial renal glucosuria, a genetic disease characterized by chronic glucosuria in the absence of hyper-

Figure 1. SGLT2 is responsible for the majority of glucose reabsorption in the renal proximal tubule.3

Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Drug Discovery (Chao EC, Henry RR. SGLT2 inhibition—a novel strategy for diabetes treatment. Nat Rev Drug Discov. 2010;9(7):551–559), Copyright 2010. Abbreviations: SGLT, sodium glucose co-transporter. © Hospital Practice, Volume 42, Issue 3, August 2014, ISSN – 2154-8331 97 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Stephen Brunton and Timothy S. Reid


Figure 2. The threshold for UGE is increased in patients with T2DM compared with healthy individuals.61

From Postgraduate Medicine,Vol. 126, Davidson JA, Kuritzky L. Sodium glucose co-transporter 2 inhibitors and their mechanism for improving glycemia in patients with type 2 diabetes, In Press, Copyright 2014, with permission from JTE Multimedia, LLC. Abbreviations: CANA, canagliflozin; RTG, renal threshold for glucose excretion; T2DM, type 2 diabetes mellitus; UGE, urinary glucose excretion.

glycemia due to a mutation in the gene encoding SGLT2, have supported the development of SGLT2 inhibitors. In individuals with familial renal glucosuria, no notable clinical issues have been reported, and the condition is generally regarded as benign.23 The phenotype associated with familial renal glucosuria has not been evaluated comprehensively, so limited clinical characteristics have been reported and are primarily based on case studies and anecdotal evidence.24 Occasionally, there have been examples of episodic dehydration during pregnancy and starvation, as well as increased incidences of urinary tract infections, natriuresis, and volume depletion reported in patients with severe forms of familial renal glucosuria, but in general most patients have a favorable prognosis.23 This suggests that UGE related to pharmacologic inhibition of SGLT2 may be generally well tolerated. Taken together, these examples demonstrate that inhibiting SGLT2 provides an appealing therapeutic strategy among the range of treatments available for T2DM.

SGLT2 Inhibition for Lowering Plasma Glucose in Patients With T2DM

By inhibiting renal glucose reabsorption, SGLT2 inhibitors lower RTG and the renal glucose resorptive capacity, resulting in glucose being excreted in the urine instead of reabsorbed into the bloodstream. This leads to lowered plasma glucose, without interfering with renal filtration of glucose at the glomerulus.3,20,25 This mechanism depends on the ability to filter excess glucose, 98

which is related to an individual’s renal function status. Increased UGE (80–120 g/day)26 with SGLT2 inhibition is also associated with a mild osmotic diuresis that may contribute to a lowering of blood pressure (BP), as well as a net loss of calories (4 kcal/g glucose excreted; 320–480 kcal/day) that results in body weight reduction. In studies of canagliflozin, reductions in RTG (to 80–100 mg/dL) occur at a level above the usual threshold for hypoglycemia (ie, 70 mg/dL),20,27 suggesting that SGLT2 inhibition may be associated with a low inherent risk of hypoglycemia. Diabetes results in increased glucose and sodium reabsorption by the SGLT2 transporter in the proximal tubule. Increased sodium reabsorption in the proximal tubule leads to a reduction in sodium delivery to the juxtaglomerular apparatus and an enhancement of the tubuloglomerular feedback reflex, resulting in renal afferent arteriole vasodilation, elevated intraglomerular pressure, and increased glomerular filtration rate.2 Treatment with SGLT2 inhibitors could therefore benefit diabetic patients by both normalizing plasma glucose concentration and increasing sodium delivery to the distal tubule.2 Due to their targeted effects in the kidney, SGLT2 inhibitors provide a treatment option that can complement the glycemic effects of other AHAs that lower plasma glucose via different mechanisms of action (eg, stimulate insulin secretion or enhance insulin sensitivity) when used concomitantly in patients with T2DM.3



Efficacy and Safety of Canagliflozin: Findings From Clinical Studies

The efficacy and safety of canagliflozin have been evaluated in phase 3 clinical studies of up to 104 weeks in patients with T2DM on a variety of background diabetes treatment regimens.28–35 These clinical trials enrolled . 10 000 patients with T2DM and evaluated canagliflozin as a monotherapy, dual therapy, and triple therapy. This review focuses on the primary outcomes from core treatment periods of 26 or 52 weeks; data from longer extension periods will be the focus of future reviews.


Efficacy

Canagliflozin 100 and 300 mg significantly reduced hemoglobin A1c (HbA1c), body weight, and systolic BP compared with placebo after 26 weeks of treatment in studies of canagliflozin as monotherapy,33 add-on to metformin,30 and addon to metformin plus sulfonylurea34 (Figure 3). In 52-week active-comparator studies as add-on to metformin, both canagliflozin doses demonstrated noninferiority, and canagliflozin 300 mg demonstrated superiority, to sitagliptin30 and glimepiride29 in HbA1c-lowering (Figure 4A); canagliflozin also provided reductions in fasting plasma glucose compared with sitagliptin and glimepiride. Similarly, as add-on to metformin plus sulfonylurea, canagliflozin 300 mg demonstrated superiority to sitagliptin in HbA1c-lowering.31 In addition, both canagliflozin doses significantly reduced body weight and lowered systolic BP compared with sitagliptin30,31 and glimepiride29 (Figure 4B,C). Reductions in body weight are likely associated with the caloric deficit caused by increased UGE. Based on the estimated caloric loss of 380 to 420 kcal/day and assuming no dietary changes, a mathematical model estimates that weight loss of 5.5 to 7.0 kg should occur over 26 weeks. The weight loss seen across studies of canagliflozin is lower than this estimate, suggesting that a combination of reduced energy expenditure and increased food intake may inhibit further weight loss, similar to observations with another SGLT2 inhibitor, empagliflozin.36,37 Body composition analyses have shown that weight loss with canagliflozin is primarily attributed to loss of fat mass (approximately two-thirds).29 Reductions in systolic BP may be attributed to the diuretic effect of canagliflozin, leading to intravascular volume reduction, or alterations in sodium reabsorption associated with canagliflozin treatment. In addition, weight loss contributes to reductions in BP with canagliflozin, with 40% of the reduction in systolic BP found to be associated with weight loss.38

In studies in which β-cell function was assessed, treatment with canagliflozin has been shown to improve indices of β-cell function in patients with T2DM over 26 to 52 weeks, including measures based on fasting blood samples (Homeostasis Model Assessment [HOMA2-%B] and proinsulin/C-peptide ratio) and measures of β-cell function obtained from a mixed meal tolerance test (including the ratio of C-peptide area under the curve and model-based measures of β-cell function).27,31,33,34,39 Because the deterioration of β-cell function drives the progression of T2DM,4,40 it will be important to assess whether the improvement in β-cell function observed in these studies is sustained with longer treatment duration and whether the improvements in β-cell function help provide a more durable treatment effect than has been observed with other AHAs.41 Changes in fasting plasma lipids in a pooled data set from four 26-week, placebo-controlled, phase 3 studies of canagliflozin are shown in Table 1. Across 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).28–31,33,34 Small, dose-related increases in non–HDL-C that were smaller than the observed increases in LDL-C were seen across studies. Small increases in the LDL-C/HDL-C ratio were observed with canagliflozin in some studies,28,29,31,33,34 whereas small decreases in the LDL-C/HDL-C ratio were seen in other studies.30,33 In 2 studies in which apolipoprotein B was assessed in subsets of patients, small increases were seen with canagliflozin compared with placebo.30,33 Canagliflozin has also demonstrated efficacy in improving glycemic control in special patient populations. In a study in patients with T2DM and moderate renal impairment (estimated glomerular filtration rate [eGFR] $ 30 and , 50 mL/min/1.73 m2), canagliflozin significantly reduced HbA1c and was associated with decreases in body weight and systolic BP compared with placebo; however, consistent with its mechanism of action, the magnitude of reductions in HbA1c (−0.33%, −0.44%, and −0.03% with canagliflozin 100 and 300 mg and placebo, respectively) and body weight (−1.2% [−1.2 kg], −1.5% [−1.4 kg], and 0.3% [0.2 kg], respectively) were less than those seen in other studies in patients with normal or mildly impaired renal function (Figure 3A,B).35 In a study in older patients with T2DM (aged 55–80 years), canagliflozin improved glycemic control and reduced body weight and systolic BP compared with placebo; however, the magnitude of these reductions was smaller than those observed in younger patients with T2DM.28 Among patients with T2DM and a history or high risk of cardiovascular

© Hospital Practice, Volume 42, Issue 3, August 2014, ISSN – 2154-8331 99 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Stephen Brunton and Timothy S. Reid Figure 3. The 26-week results from PBO-controlled trials of CANA 100 and 300 mg as monotherapy, add-on to MET, and add-on to MET + SU show mean changes from baseline in (A) HbA1c, (B) body weight, and (C) SBP.30,33,34,61


A

B

(Continued)

100


Canagliflozin for T2DM Figure 3 (Continued)


C

*P , 0.001 vs PBO. From Postgraduate Medicine,Vol. 126, Davidson JA, Kuritzky L. Sodium glucose co-transporter 2 inhibitors and their mechanism for improving glycemia in patients with type 2 diabetes, In Press, Copyright 2014, with permission from JTE Multimedia, LLC. Abbreviations: CANA, canagliflozin; HbA1c, hemoglobin A1c; LS, least squares; MET, metformin; PBO, placebo; SBP, systolic blood pressure; SE, standard error; SU, sulfonylurea.

disease enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS), canagliflozin 100 and 300 mg compared with placebo were evaluated in a prespecified substudy of patients on background insulin with or without other AHAs ($ 30 IU/day; mean dose at baseline of 83 IU/day; ∼70% of these patients were on a background regimen of basal and bolus insulin combined; mean baseline eGFR of 75 mL/min/1.73 m2).5,42 Relative to placebo, canagliflozin 100 and 300 mg provided reductions in HbA1c (−0.65% and −0.73%, respectively; P , 0.001), body weight (−1.9% and −2.4%, respectively; P , 0.001), and systolic BP (−2.6 and −4.4 mmHg, respectively) at 18 weeks.5 Canagliflozin has shown increased HbA1c-lowering in patients with elevated baseline HbA1c. In a 26-week study of canagliflozin as monotherapy, canagliflozin 100 and 300 mg provided reductions from baseline in HbA1c of −2.13% and −2.56%, respectively, in a subgroup of patients with baseline HbA1c . 10.0% and # 12.0%.33 Canagliflozin 100 and 300 mg as monotherapy were also associated with smaller HbA1c reductions in subgroups with higher baseline HbA1c compared with placebo (HbA1c , 8.0%: −0.42%, −0.65%, and 0.24%; HbA1c $ 8.0% and , 9.0%: −1.07%, −1.30%, and 0.13%; HbA1c $ 9.0%: −1.29%, −1.83%, and −0.18%,

respectively).33 Similarly, in a 52-week clinical trial of canagliflozin as an add-on to metformin plus sulfonylurea, canagliflozin 300 mg provided greater HbA1c reductions in subgroups with higher baseline HbA1c compared with sitagliptin 100 mg (HbA1c , 8.0%: −0.57% and −0.31%; HbA1c $ 8.0% to , 9.0%: −1.15% and −0.73%; HbA1c $ 9.0%: −1.99% and −1.44%, respectively).31 Together, these results demonstrate greater glycemic improvements in patients with elevated baseline HbA1c consistent with observations with other AHAs.43

Safety

Canagliflozin was generally well tolerated in patients with T2DM; incidences of serious adverse events (AEs) and AEs leading to treatment discontinuation were generally low across the phase 3 program (Table 2).28–35 Canagliflozin was associated with increased incidences of specific AEs likely related to its mechanism of action, such as genital mycotic infections and AEs related to osmotic diuresis (eg, pollakiuria [increased urine frequency], polyuria [increased urine volume], and thirst); these AEs have also been observed with other SGLT2 inhibitors.9,44–47 In a pooled analysis of data from four 26-week, phase 3 studies of canagliflozin, genital


Stephen Brunton and Timothy S. Reid Figure 4. The 52-week results from active-controlled trials of CANA 100 and 300 mg versus GLIM as add-on to MET, CANA 100 and 300 mg versus SITA as add-on to MET, and CANA 300 mg versus SITA as add-on to MET + SU show mean changes from baseline in (A) HbA1c, (B) body weight, and (C) SBP.29–31,61


A

B

(Continued)

102


Canagliflozin for T2DM Figure 4. (Continued)


C

*P , 0.0001 vs GLIM. † P , 0.001 vs SITA 100 mg. From Postgraduate Medicine,Vol. 126, Davidson JA, Kuritzky L. Sodium glucose co-transporter 2 inhibitors and their mechanism for improving glycemia in patients with type 2 diabetes, In Press, Copyright 2014, with permission from JTE Multimedia, LLC. Abbreviations: CANA, canagliflozin; GLIM, glimepiride; HbA1c, hemoglobin A1c; LS, least squares; MET, metformin; SBP, systolic blood pressure; SE, standard error; SITA, sitagliptin; SU, sulfonylurea.

mycotic infections were more common with canagliflozin 100 and 300 mg compared with placebo in women (10.4%, 11.4%, and 3.2%, respectively) and men (4.2%, 3.7%, and 0.6%, respectively); these events were mild or moderate in severity, none were serious, and they generally did not lead to study discontinuation.5,48 Patients with a history of genital mycotic infection were at increased risk of genital mycotic infection with canagliflozin (5.7% vs 0.7% of men with genital mycotic infections were uncircumcised vs circumcised, respectively). Overall, 8.0%, 9.1%, and 2.9% of women and 3.7%, 2.5%, and 0.6% of men experienced 1 genital mycotic infection with canagliflozin 100 and 300 mg and placebo, respectively; few patients experienced . 1 genital mycotic infection (women: 2.3% with canagliflozin, 0.3% with placebo; men: 0.9% with canagliflozin, 0% with placebo).48 Most genital mycotic infections were successfully treated using oral or topical antifungal and/or antibacterial agents.48 In the same pooled population, urinary tract infections occurred in 5.9% and 4.3% of patients receiving canagliflozin 100 and 300 mg, respectively, compared with 4.0% of those

receiving placebo.49 These AEs were generally mild or moderate in intensity and infrequently were serious or led to study discontinuation, and canagliflozin was not associated with an increased incidence of upper urinary tract infections compared with placebo. In addition, the incidence of urinary tract infections with canagliflozin was 7.9%, 4.9%, and 6.3% with canagliflozin 100 and 300 mg and sitagliptin, respectively, as add-on to metformin, and 4.0% and 5.6% with canagliflozin 300 mg and sitagliptin, respectively, as add-on to metformin plus sulfonylurea over 52 weeks.30,31 From pooled data obtained from 8 placebo- and active-controlled studies of canagliflozin, the incidence of volume depletion AEs (eg, hypotension, dizziness postural, orthostatic hypotension, syncope, and dehydration) with canagliflozin 100 and 300 mg versus comparator was generally low (2.3%, 3.4%, and 1.5%, respectively), but higher in patients aged $ 75 years (4.9%, 8.7%, and 2.6%, respectively), patients with moderate renal impairment (eGFR , 60 mL/min/1.73 m2; 4.7%, 8.1%, and 2.5%, respectively), and patients taking loop diuretics (3.2%, 8.8%, and 4.7%, respectively).5




Table 1. Changes in Fasting Plasma Lipids in the Pooled PBO-Controlled Studies at Week 2660 Parametera

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

Baseline triglycerides, mg/dL Change, mg/dL Change, % Baseline HDL-C, mg/dL Change, mg/dL Change, % Baseline LDL-C, mg/dL Change, mg/dL Change, % Baseline non–HDL-C, mg/dL Change, mg/dL Change, % Baseline LDL-C/HDL-C, mg/mg Change, mg/mg Change, %

185.8 -0.4 7.6 45.4 1.3 4.0 109.5 -2.2 1.3 146.5 -2.2 0.7 2.5 -0.12 -0.8

182.1 -9.7 2.4 45.9 3.7 9.4 106.6 2.2 5.7 142.9 -0.03 2.2 2.5 -0.13 -1.4

180.3 -19.5 0.0 46.3 4.1 10.3 104.4 6.0 9.3 139.5 2.9 4.3 2.4 -0.07 0.8

Data are mean baseline values and LS mean changes from baseline. Abbreviations: CANA, canagliflozin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LS, least squares; PBO, placebo. a

Across studies, canagliflozin was associated with small, transient reductions in eGFR that are believed to be the result of intra-renal hemodynamic changes50; these reductions generally stabilized or attenuated over time. As add-on to metformin, canagliflozin 100 and 300 mg were associated with greater eGFR reductions (from baseline ∼90 mL/min/1.73 m2) compared with glimepiride over 52 weeks (−1.7, −3.0, and −5.1 mL/min/1.73 m2, respectively); with both doses of canagliflozin, decreases in eGFR were noted at week 4 but stabilized from weeks 12 to 52, whereas glimepiride was associated with a progressive reduction in eGFR (Figure 5).5,29 Corresponding small reductions in the urinary albumin-creatinine ratio were seen with canagliflozin 100 and 300 mg (−0.1 and −0.9 g/mol, respectively) compared with a small increase with glimepiride (0.7 g/mol).29 Similar small reductions in eGFR (from baseline ∼88 mL/min/1.73 m2) were seen with canagliflozin 300 mg compared with sitagliptin (−4.6 and −5.1 mL/min/1.73 m2, respectively) as add-on to metformin plus sulfonylurea.5,31 In a pooled analysis of data from placebo-controlled studies of patients with normal or mildly impaired renal function over 26 weeks, canagliflozin 100 and 300 mg relative to placebo provided reductions in eGFR (−2.3, −3.4, and −1.6 mL/min/1.73 m2, respectively) with commensurate increases in serum creatinine (0.02, 0.03, and 0.01 mg/dL, respectively).5,60 The incidence of renal-related AEs was low and similar across groups (0.6%, 1.7%, and 0.6% with canagliflozin 100 and 300 mg and placebo, respectively), and AEs of blood creatinine increase occurred in few patients (1 [0.1%], 4 [0.5%], and 1 [0.2%] patients, respectively).5 104

In the study in patients with moderate renal impairment (eGFR $ 30 and , 50 mL/min/1.73 m2), the mean changes from baseline to week 26 in eGFR (−3.6, −4.0, and −1.5 mL/min/1.73 m2, respectively) and serum creatinine (0.16, 0.18, and 0.07 mg/dL, respectively) were slightly larger compared with patients who had normal or mildly impaired renal function assessed in the pooled population of patients from the placebo-controlled studies.5 Canagliflozin was generally associated with only small changes from baseline in serum electrolytes, including potassium. In pooled analyses, the proportion of patients meeting outlier criteria for elevated potassium (ie, . 5.4 mmol/L and . 15% increase from baseline) at any time post-baseline with canagliflozin 100 and 300 mg and placebo were 4.5%, 6.8%, and 4.7%, respectively, among patients with eGFR $ 60 mL/min/1.73 m2; and 5.2%, 9.1%, and 5.5%, respectively, among patients with eGFR $ 45 and , 60 mL/min/1.73 m2.51 These changes were transient, as reflected by the proportion of patients meeting outlier criteria for elevated potassium at the last post-baseline value with canagliflozin 100 and 300 mg and placebo among patients with eGFR $ 60 mL/min/1.73 m2 (0.9%, 1.3%, and 0.3%, respectively) and $ 45 and , 60 mL/min/1.73 m2 (1.9%, 1.7%, and 3.1%, respectively). Adverse events related to elevated potassium were reported in 0.8%, 0.7%, and 0.2% patients with eGFR $ 60 mL/min/1.73 m2 with canagliflozin 100 and 300 mg and placebo, respectively; the incidence was 1.4%, 2.1%, and 1.5%, respectively, in patients with eGFR $ 45 and , 60 mL/min/1.73 m2.51 Only canagliflozin 300 mg was infrequently associated with an increased inci-



Table 2. Safety of CANA in T2DM Parameter

CANA28–31,33–35

Overall safety and tolerability Genital mycotic infections

• Generally well tolerated, with low incidences of serious AEs and AEs leading to discontinuation • Higher incidence versus PBO, SITA 100 mg, and GLIM • Few events led to discontinuation • Generally mild or moderate in intensity and responded to standard treatments • Higher risk in patients with prior genital mycotic infection and in uncircumcised males • Low recurrence rate in women and men • Higher incidence versus PBO and GLIM, and similar incidence versus SITA 100 mg • Generally mild or moderate in intensity • Not associated with upper UTIs or serious UTIs, and few led to study discontinuation • Incidence generally low, but higher than with PBO and SITA 100 mg • Few events led to study discontinuation • Incidence generally low, dose-dependent • Few events leading to study discontinuation • Increased risk in patients aged $ 75 years, patients with moderate renal impairment, and patients taking loop diuretics • Low incidence, similar to that with PBO, as monotherapy • Significantly lower incidence versus GLIM, similar low incidence versus SITA 100 mg as add-on to MET • Incidence similar to that with SITA 100 mg as add-on to MET + SU despite greater HbA1c improvement seen with CANA • Moderate increases in blood urea nitrogen • Small decreases in eGFR with nadir observed early in treatment and values trending toward baseline for duration of study; commensurate increases in serum creatinine • Moderate reductions in alanine aminotransferase and gamma glutamyl transferase, and moderate increases in bilirubin • Small increases in hemoglobin • Moderate reduction in serum urate

UTIs


Osmotic diuresis–related AEs (eg, pollakiuria, polyuria, thirst) Volume depletion–related AEs (eg, orthostatic hypotension, dizziness postural) Hypoglycemia

Clinical laboratory parameters

Safety in special populations Patients with moderate renal impairment

Older patients

• Similar AE rates versus PBO • Slightly higher incidences of UTIs (8% with CANA 300 mg versus 6% with both CANA 100 mg and placebo) • Low incidence of AEs related to osmotic and volume depletion that was slightly higher with CANA versus PBO • Transient reductions in eGFR that were largest at week 3 and attenuated toward baseline over time (-9.1%, -10.1%, and -4.5% with CANA 100 and 300 mg and PBO, respectively, at week 26) • Median percent reductions in ACR versus PBO (approximately -30%, -21%, and -8% with CANA 100 and 300 mg and PBO, respectively, at week 26) • Safety profile consistent with other studies

Abbreviations: ACR, albumin-creatinine ratio; AE, adverse event; CANA, canagliflozin; eGFR, estimated glomerular filtration rate; GLIM, glimepiride; HbA1c, hemoglobin A1c; MET, metformin; PBO, placebo; SITA, sitagliptin; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; UTI, urinary tract infection.

dence of elevated potassium in patients with eGFR $ 45 and , 60 mL/min/1.73 m2.51 Notably, canagliflozin 300 mg is not indicated for use in these patients, with canagliflozin treatment limited to the 100-mg dose in patients with eGFR $ 45 and , 60 mL/min/1.73 m2 in the United States.5 The incidence of hypoglycemia was generally low with canagliflozin in patients not on background treatment with insulin or sulfonylurea (AHAs associated with increased risk of hypoglycemia; Table 2).29,30,32,33 Both canagliflozin doses were associated with significantly lower incidences of hypoglycemia compared with glimepiride in patients on background metformin treatment29; however, the incidence of hypoglycemia was low and similar with canagliflozin and sitagliptin in patients on background metformin.30 In patients receiving background metformin plus sulfonylurea, the inci-

dence of hypoglycemia was higher than in patients receiving metformin alone, but similar with canagliflozin 300 mg and sitagliptin 100 mg despite a larger HbA1c improvement with canagliflozin 300 mg.31 In patients on insulin and/or sulfonylurea therapy, an increased incidence of hypoglycemia has been observed with canagliflozin relative to placebo.28,34,35 This is consistent with previous observations of increased hypoglycemia incidence with agents not associated with hypoglycemia when used in combination with insulin/sulfonylurea.52–56 In patients with moderate renal impairment35 and in older patients (aged 55–80 years),28 canagliflozin was well tolerated, with a safety profile consistent with that observed in other phase 3 studies. The effect of canagliflozin on cardiovascular safety is important because many patients with T2DM are at elevated




Figure 5. Canagliflozin as add-on to metformin (MET) is associated with reductions in estimated glomerular filtration rate (eGFR) that return toward baseline over 52 weeks.29

Reprinted from The Lancet,Vol. 382, Cefalu WT, 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, 941−950, Copyright 2013, with permission from Elsevier. Abbreviations: CANA, canagliflozin; GLIM, glimepiride; SE, standard error.

risk of or have cardiovascular disease. An interim metaanalysis of cardiovascular outcomes using data from patients with T2DM enrolled in phase 2 or phase 3 studies of canagliflozin (N = 9632), of which 4327 patients were enrolled in the CANVAS trial, showed a hazard ratio (95% confidence interval) of 0.91 (0.68–1.22) for canagliflozin compared with placebo for the composite end point of time to cardiovascular event (eg, cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, unstable angina requiring hospitalization).57,58 The long-term effects of canagliflozin on cardiovascular safety will be evaluated in the ongoing CANVAS and CANVAS-R trials.

Conclusion

The SGLT2 inhibitors are a novel class of AHAs with a distinct, renally mediated, and insulin-independent mechanism of action. Treatment with SGLT2 inhibitors increases glucosuria and promotes the excretion of excess glucose in the urine, rather than reabsorption into the bloodstream. Clinical findings from phase 3 studies in patients with T2DM have demonstrated the efficacy of the SGLT2 inhibitor canagliflozin in improving glycemic control and reducing body weight and BP as monotherapy or as add-on to other AHAs. Canagliflozin treatment was also effective in improving glycemic control in special T2DM patient populations, including patients with moderate renal impairment (eGFR $ 30 and , 50 mL/min/1.73 m2) and older patients (aged 106

55–80 years). Canagliflozin is generally well tolerated, with increased incidences of specific AEs that are associated with the SGLT2 inhibitor class. In addition to lowering plasma glucose levels, inhibition of renal glucose reabsorption with an SGLT2 inhibitor might also be expected to have a beneficial renoprotective action2; however, SGLT2 inhibitors are not currently indicated for renoprotection. The potential renoprotective benefits of canagliflozin will be evaluated in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial (ClinicalTrials.gov, identifier NCT02065791). With their recent approval in the United States, SGLT2 inhibitors have become an option for primary care clinicians for the treatment of patients with T2DM. The current American Association of Clinical Endocrinologists treatment algorithm for T2DM has incorporated SGLT2 inhibitors for use at any point after diet and exercise are implemented (ie, as a monotherapy or in combination with other AHAs for additive efficacy in terms of glycemic control).59 Taken together with the favorable efficacy and safety findings across clinical studies, this suggests that canagliflozin is a useful treatment option for a broad range of patients with T2DM.

Acknowledgments

Editorial support was provided by Cherie Koch, PhD, of MedErgy, and was funded by Janssen Scientific Affairs, LLC. The authors retained full editorial control over the content



of the article.

Conflict of Interest Statement

Stephen Brunton, MD, has been an advisor and speaker for Janssen, Novo Nordisk, Astra Zeneca, and Abbot. Timothy S. Reid, MD, has served as a consultant and speaker for BMS/Astra Zeneca, Novo Nordisk, Sanofi-Aventis, Janssen, Boehringer Ingelheim/Lilly, and Lilly.


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Dapagliflozin: A Sodium Glucose Cotransporter 2 Inhibitor for the Treatment of Diabetes Mellitus.

Renal threshold for glucose reabsorption predicts diabetes improvement by sodium-glucose cotransporter 2 inhibitor therapy.

Nonclinical safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin.

Canagliflozin: A Novel SGLT2 Inhibitor for Type 2 Diabetes Mellitus.

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