The Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Treatment of Type 2 Diabetes

Clinical Therapeutics/Volume ], Number ], 2015

The Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Treatment of Type 2 Diabetes Karen Whalen, PharmD, BCPS, CDE1; Shannon Miller, PharmD, BCACP2; and Erin St. Onge, PharmD2 1

Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, Florida; and 2Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Orlando Campus, Orlando, Florida ABSTRACT Purpose: Diabetes is a chronic metabolic disorder characterized by hyperglycemia that results from insulin resistance, diminished or absent insulin secretion, or both. Approximately one-half of patients with diabetes fail to achieve acceptable glycemic control. Consequently, morbidity and mortality associated with diabetes is high, resulting from complications such as cardiovascular disease and nephropathy. The sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of medications for the treatment of type 2 diabetes. This article provides an overview of efficacy and safety data for the SGLT2 inhibitors and outlines their role in the management of diabetes. Methods: Relevant articles were identified through searches of PubMed and International Pharmaceutical Abstracts by using the key terms canagliflozin, dapagliflozin, empagliflozin, and sodium-glucose co-transporter 2 inhibitor. A review of bibliographies of retrieved articles was also performed to identify additional references. All identified trials published in English and that involved the efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes were reviewed. Findings: The SGLT2 inhibitors improve glucose control by increasing urinary glucose excretion. Effectiveness is decreased in the presence of renal dysfunction. These agents are efficacious as monotherapy and add-on therapy for patients with type 2 diabetes uncontrolled on metformin, sulfonylureas, insulin, and other antihyperglycemic combinations. The SGLT2 inhibitors lower glycosylated hemoglobin by 0.5% to 1% and fasting plasma glucose by
15 to 35 mg/dL, depending on the agent and the dosage used, and are also associated with modest reductions in weight (1.5 to 3.5 kg) and systolic blood pressure

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(3 to 5 mm Hg). Genital mycotic infections and increased urination, owing to the mechanism of action, are the most common adverse effects. In general, the class is well tolerated, and the risk of hypoglycemia is low. Implications: With their unique mechanism of action and good safety and tolerability profiles, the SGLT2 inhibitors are an important addition to existing treatments for type 2 diabetes. Because of the lack of data with this class of drugs when current treatment guidelines for diabetes were published, the SGLT2 inhibitors are recommended as second- or third-line therapies for diabetes. Forthcoming data on the longterm efficacy and safety profile of these agents should help to solidify the role of SGLT2 inhibitors in the management of diabetes. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: canagliflozin, dapagliflozin, empagliflozin, sodium-glucose co-transporter 2 inhibitor.

INTRODUCTION Diabetes is a chronic metabolic disorder characterized by hyperglycemia that results from insulin resistance, diminished or absent insulin secretion, or both. Diabetes is estimated to affect 29.1 million Americans and close to 350 million people worldwide.1,2 The most common form of diabetes, accounting for 90% to 95% of cases, is type 2 diabetes mellitus (T2DM), or diabetes attributed to insulin resistance. Chronic complications of diabetes include both microvascular Accepted for publication March 5, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.03.004 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics complications such as nephropathy, neuropathy, and retinopathy and macrovascular complications such as heart disease and stroke. Cardiovascular (CV) risk is significant in T2DM, with heart disease or stroke claiming the lives of 2 of 3 patients.2,3 Substantial evidence indicates that controlling blood glucose prevents the risk or reduces progression of microvascular complications.4,5 Furthermore, controlling other risk factors such as hypertension and dyslipidemia reduces the risk of both nephropathy and retinopathy and is paramount to decreasing the occurrence of CV disease in diabetes. First-line therapy for the management of T2DM generally involves lifestyle modifications, including diet and exercise, along with metformin.6 Other oral medications for the treatment of T2DM have traditionally included sulfonylureas, meglitinides, thiazolidinediones (TZDs), dipeptidyl-peptidase-4 inhibitors, α-glucosidase inhibitors, bromocriptine, and colesevelam. Injectable agents such as various forms of insulin, glucagon-like peptide-1 (GLP-1) receptor agonists, and amylin analogs are also used for the treatment of T2DM. Despite the availability of a wide variety of medications, almost one-half of patients with diabetes fail to achieve acceptable glycemic control.7 Thus, the search for effective medications for diabetes continues. In 2013 a new class of antihyperglycemic medications, the sodium-glucose co-transporter 2 (SGLT2) inhibitors, entered the market. Canagliflozin was the first of these agents to obtain approval by the US Food and Drug Administration (FDA) in March 2013. Subsequently, the FDA approved dapagliflozin in January 2014 and empagliflozin in August 2014. Each of these agents is approved for the treatment of T2DM in adults.8–10 This article provides an overview of efficacy and safety data for the SGLT2 inhibitors and outlines their role in the management of T2DM.

METHODS Relevant articles were identified through searches of PubMed (publication date range: 1966–November 2014) and International Pharmaceutical Abstracts (publication date range: January 1970–November 2014) by using the key terms canagliflozin, dapagliflozin, empagliflozin, and sodium-glucose co-transporter 2 inhibitor. A review of bibliographies of retrieved articles was also performed to identify additional references. All identified trials published in English and that involved efficacy and safety of

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SGLT2 inhibitors in the treatment of T2DM were reviewed.

RESULTS Clinical Pharmacology Under normal circumstances, the adult kidney filters
180 g of glucose per day.11 Almost all of the glucose filtered by the kidney is reabsorbed and returned to the systemic circulation via the SGLT proteins SGLT2 and SGLT1. Even though plasma glucose levels are elevated in T2DM, the kidneys continue to reabsorb glucose through the SGLT proteins, thereby contributing to hyperglycemia. SGLT2 is a low-affinity, high-capacity transporter found exclusively in the proximal renal tubule. It is responsible for reabsorption of 90% of glucose filtered by the kidney. SGLT1 is a high-affinity, low-capacity transporter located further along the proximal tubule, and it reabsorbs the remaining glucose.12 SGLT1 is also expressed in the brush border of the small intestine where it plays a significant role in glucose absorption. The available SGLT2 inhibitors differ in their relative selectivity for SGLT2 versus SGLT1. For instance, empagliflozin is the most selective for SGLT2 (42500:1), followed by dapagliflozin (41200:1) and canagliflozin (4250:1).13 The clinical significance of SGLT2 selectivity is not fully established. Agents with lower selectivity for SGLT2 may transiently inhibit SGLT1-mediated glucose absorption in the small intestine, thereby reducing postprandial glucose.14 The SGLT2 inhibitors exert their main pharmacologic action by preferentially inhibiting SGLT2. Inhibition of SGLT2 decreases reabsorption of glucose, leading to an increase in urinary glucose excretion (UGE) and a reduction in plasma glucose levels. The increased UGE seen with SGLT2 inhibitors also results in a loss of 200 to 300 kcal/d, which may contribute to modest weight loss observed with these agents.12 In addition, modest reductions in systolic blood pressure may occur, likely attributable to the mild osmotic diuresis produced by this class. Because SGLT2 inhibitors depend on sufficient glomerular filtration to be effective, they subsequently work best in patients with normal renal function or mild renal impairment.15 Dapagliflozin should not be used in patients with an estimated glomerular filtration rate (eGFR) of o60 mL/min/1.73 m2. Canagliflozin and empagliflozin should not be used if eGFR is o45 mL/min/1.73 m2.8–10 Volume ] Number ]

K. Whalen et al. No dosing considerations are required for hepatic impairment. All 3 agents are administered once daily in the morning. Dapagliflozin and empagliflozin may be administered with or without food.9,10 Although canagliflozin may be taken without regard to food, the product information recommends administration before the morning meal, because the SGLT1 activity of this agent may delay intestinal glucose absorption and reduce postprandial hyperglycemia.8,14

Drug Interactions Drug interaction studies that examined the concurrent use of the SGLT2 inhibitors with other antihyperglycemics such as metformin and sulfonylureas have revealed no clinically significant pharmacokinetic changes.8,16–19 When dapagliflozin and glimepiride are used together, there may be a slight increase in the risk of hypoglycemia; therefore, patients should be monitored appropriately.17 Dapagliflozin was also investigated in combination with pioglitazone and sitagliptin.16 Results of these pharmacokinetic studies found that no dosage adjustment is needed for either medication. The combination of empagliflozin with the dipeptidyl-peptidase-4 inhibitors sitagliptin or linagliptin20,21 was examined. Although sitagliptin slightly increases exposure to empagliflozin, these changes were not considered clinically relevant. The concurrent administration of the SGLT2 inhibitors with simvastatin, warfarin, and digoxin revealed no clinically significant interactions, with the exception of the combination of canagliflozin and digoxin.8,22–25 If administered together, digoxin levels should be closely monitored, because canagliflozin increases the exposure to digoxin.8 The use of the diuretic hydrochlorothiazide in combination with canagliflozin or empagliflozin was also studied with no clinically relevant interactions reported.26,27 Likewise, dapagliflozin and empagliflozin were studied in combination with antihypertensives such as valsartan, verapamil, and ramipril with no clinically significant effects noted.22,25 Dapagliflozin is mainly metabolized via uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9). Rifampin, an inducer of UGT1A9, reduces exposure to dapagliflozin, and mefenamic acid, a UGT1A9 inhibitor, enhances exposure. However, changes in dapagliflozin levels are not clinically meaningful, and no dosage adjustments are warranted.9,28 The concurrent

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use of canagliflozin and rifampin was found to decrease the efficacy of canagliflozin. Therefore, an increase in the dose of canagliflozin may be required when coadministered with rifampin and other UGT inducers, including phenytoin, phenobarbital, and ritonavir.8,29 Exposure of canagliflozin is increased with cyclosporine and probenecid; however, these interactions are not clinically relevant.30 No clinically meaningful interaction was observed when empagliflozin or canagliflozin were used with oral contraceptives that contain ethinyl estradiol and levonorgestrel.8,31 The mechanism of action of the SGLT2 inhibitors relies heavily on adequate kidney function. Drugs that affect kidney function (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, NSAIDs) should be used cautiously, because a decrease in the effect of the SGLT2 inhibitors may be expected. Although no significant pharmacokinetic interaction exists with diuretics and the SGLT2 inhibitors, pharmacodynamic interactions may occur. Patients who are particularly sensitive to volume changes should be monitored closely for signs and symptoms of dehydration and electrolyte abnormalities when SGLT2 inhibitors are combined with diuretics.29 Canagliflozin use may lead to an increase in serum potassium levels.32 Potassium levels should be monitored in patients who take canagliflozin in combination with other medications that can increase potassium. Despite similar mechanisms of action, no evidence supports alterations in potassium with empagliflozin or dapagliflozin.

Clinical Trials Canagliflozin, dapagliflozin, and empagliflozin were each studied as monotherapy for T2DM and as add-on therapy with other oral antihyperglycemic agents and/ or insulin. A summary of clinical trials performed with canagliflozin, dapagliflozin, and empagliflozin is provided in Table I,33–39 Table II,40–47 and Table III,48–55 respectively. Selected trials for each agent are reviewed below.

Canagliflozin Clinical Trials Stenlöf et al33 evaluated the efficacy and safety profile of canagliflozin monotherapy in a randomized, double-blind, placebo-controlled phase 3 study. Eligible subjects included patients with T2DM who were 18 to 80 years of age and had a glycosylated hemoglobin (HbA1c) between 7% and 10% on no

3

Study Stenlöf et al33,34 Main study (N = 584)

High glycemic substudy (N ¼ 91) Extension study (N ¼ 451) Lavalle-Gonzalez35 Period I (N ¼ 1284)

Age (y)

Baseline HbA1c (%)

Duration

Background therapy

55.4

8.0

26 weeks

None

49.3

10.6

26 weeks Weeks 27–52

55.4

7.9

Period II (active-control) (N ¼ 1103)

26 weeks

MET

Weeks 27–52

Cefalu et al36 (N ¼ 1250)

56.2

7.8

52 weeks

MET

Wilding et al37 Core period (N ¼ 469)

56.8

8.1

26 weeks

MET þ SU

Extension period Volume ] Number ]

Schernthaner et al38 (N ¼ 755) Forst et al39 Core period (N ¼ 342)

Weeks 27–52 56.7

8.1

52 weeks

MET þ SU

57.4

7.9

26 weeks

MET þ PIO

Change in HbA1c (%)

Change in FPG (mg/dL)

Change in weight (kg)

mg mg mg mg

0.77† 1.03† 0.14 2.13 2.56 0.81 1.11

27.0† 34.2† 9.0 81.0 86.4 27.4 39.1

2.5† 3.4† 0.5 3.0 3.8 3.1 4.1

CANA 100 mg CANA 300 mg SITA 100 mg PBO CANA 100 mg CANA 300 mg SITA 100 mg CANA 100 mg CANA 300 mg GLIM 6–8 mg

0.79† 0.94† 0.82‡ 0.17 0.73 0.88 0.73 0.82 0.93 0.81

27.0† 37.8† 19.8‡ 2 27.0§ 36.0§ 18.0 24.3 27.4 18.4

3.3† 3.6† 1.1‡ 1.1 3.3§ 3.7§ 1.2 3.7‖ 4.0‖ 0.7

CANA 100 mg CANA 300 mg PBO CANA 100 mg CANA 300 mg PBO CANA 300 mg SITA 100 mg

0.85† 1.06† 0.13 0.74† 0.96† 0.01 1.03 0.66

18.0† 30.6† 3.6 19.8† 27.0† 10.8 28.7§ 2.2

1.9† 2.5† 0.8 2.0 3.1 1.0 2.3§ 0.1

CANA 100 mg CANA 300 mg PBO

0.89† 1.03† 0.26

26.8† 33.2† 2.5

2.6† 3.7† 0.2

Treatment groups* CANA CANA PBO CANA CANA CANA CANA

100 mg 300 mg 100 300 100 300

(continued)

Clinical Therapeutics

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Table I. Phase 3 clinical trials with canagliflozin.

Weeks 27–52 Extension study (activecontrol) (N ¼ 289)

CANA ¼ canagliflozin; FDA ¼ Food and Drug Administration; FPG ¼ fasting plasma glucose; GLIM ¼ glimepiride; HbA1c ¼ glycosylated hemoglobin; MET ¼ metformin; PBO ¼ placebo; PIO ¼ pioglitazone; SITA ¼ sitagliptin; SU ¼ sulfonylurea. * FDA-approved dosage of canagliflozin ¼ 100 mg, 300 mg. † P o 0.001 versus placebo. ‡ P value not calculated. § P o 0.001 versus sitagliptin. ‖ P o 0.0001 versus glimepiride.

2.5‡ 3.6‡ 0.3 26.7‡ 31.5‡ 12.6 0.92‡ 1.03‡ 0.37 CANA 100 mg CANA 300 mg SITA 100 mg

Change in FPG (mg/dL) ] 2015

Study

Table I. (continued).

Age (y)

Baseline HbA1c (%)

Duration

Background therapy

Treatment groups*

Change in HbA1c (%)

Change in weight (kg)

K. Whalen et al. antihyperglycemic medication. Patients who had an HbA1c of 6.5% to 9.5% on antihyperglycemic monotherapy or metformin/sulfonylurea combination therapy were also eligible. However, the subjects on antihyperglycemic therapy underwent an 8-week washout before starting the study period. The trial also conducted a high glycemic substudy that evaluated canagliflozin in patients with an HbA1c of 10% to 12%. Exclusion criteria included a history of type 1 diabetes mellitus (T1DM) or CV disease; use of a TZD, insulin, or another SGLT2 inhibitor within 12 weeks of the study; and eGFR o50 mL/min/1.73 m2. Patients in the main study group were randomly assigned to receive canagliflozin 100 mg, canagliflozin 300 mg, or placebo daily. The high glycemic substudy group received active treatment with canagliflozin 100 mg or 300 mg. Placebo treatment was avoided in these patients because of the high HbA1c levels. The protocol required the use of rescue therapy with metformin if fasting plasma glucose (FPG) exceeded 270 mg/dL in weeks 1 through 6, 240 mg/dL in weeks 7 to 12, and 200 mg/dL in weeks 13 to 26. Patients were followed for 26 weeks. The primary outcome was the change in HbA1c from baseline. Secondary outcomes included the percentage of patients who achieved an HbA1c o7% and changes in FPG and systolic blood pressure. The main study consisted of 584 participants, and 91 patients participated in the high glycemic substudy. In the main study the changes in HbA1c at 26 weeks were 0.77%, 1.03%, and 0.14% for the canagliflozin 100-mg, canagliflozin 300-mg, and placebo groups, respectively (P o 0.001 for both canagliflozin doses versus placebo). Greater reductions in HbA1c occurred in the high glycemic subgroup, with an average reduction in HbA1c of 2.13% with canagliflozin 100 mg and 2.56% with canagliflozin 300 mg. The percentage of patients who achieved an HbA1c o7% was higher in the canagliflozin groups (44.5% canagliflozin 100 mg, 62.4% canagliflozin 300 mg versus 20.6% placebo; P o 0.001). Significant changes in FPG (27 to 34 mg/dL) and systolic blood pressure (3.7 to 5.4 mm Hg) were also noted with the active treatment groups. When the main study group was extended by an additional 26 weeks, markers of glycemic control remained similar for the canagliflozin arms.34 The incidence of adverse events was slightly greater in the canagliflozin groups, particularly the occurrence of urinary tract infections

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Volume ] Number ]

Baseline HbA1c (%)

Duration (wk)

52.6

7.92

24

Exploratory cohort (N ¼ 211)

53.2

7.82

24

High glycemic cohort (N ¼ 73)

48.1

10.82

24

Kaku et al41 (N ¼ 279)

58.1

7.48

24

None

Bailey et al42 (N ¼ 282)

53

7.9

24

None

Nauck et al43 (N ¼ 801)

58

7.7

52

MET

Bailey et al44 (N ¼ 546)

53.9

8.0

24

MET

Strojek et al17 (N ¼ 592)

59.8

8.1

24

GLIM

Rosenstock et al45 (N ¼ 420)

53.5

8.37

48

PIO

Jabbour et al46 (N ¼ 451)

54.8

7.9

48

SITA ⫾ MET

Study

Age (y)*

Ferrannini et al40 Primary cohort (N ¼ 199)

Background therapy None

Treatment groups†

Change in HbA1c (%)

DAPA 2.5 mg DAPA 5 mg DAPA 10 mg PBO DAPA 2.5 mg DAPA 5 mg DAPA 10 mg DAPA 5 mg DAPA 10 mg DAPA 5 mg DAPA 10 mg PBO DAPA 1 mg DAPA 2.5 mg DAPA 5 mg PBO DAPA 2.5–10 mg GLIP 5–20 mg DAPA 2.5 mg DAPA 5 mg DAPA 10 mg PBO DAPA 2.5 mg DAPA 5 mg DAPA 10 mg PBO DAPA 5 mg DAPA 10 mg PBO DAPA 10 mg PBO

0.58 0.77‡ 0.89§ 0.23 0.83 0.79 0.79 2.88 2.66 0.41§ 0.45§ 0.06 0.68§ 0.72§ 0.82§ 0.02 0.52¶ 0.52¶ 0.67‡ 0.7§ 0.84§ 0.3 0.58 0.63 0.82 0.13 0.95 1.21 0.54 0.5§ 0

Change in FPG (mg/dL) 15.2 24.1‡ 28.8§ 4.1 25.6 27.3 29.6 77.1 84.3 8.6§ 13.7§ 5.8 11 22§ 28§ 4.1 NR 17.8‡ 21.6§ 23.4§ 5.9 16.8 21.3 28.5 2.0 22.8 33.1 13.1 24.1§ 3.8

Change in weight (kg) 3.3‡ 2.8‡ 3.2 2.2 3.8 3.6 3.1 2.1 1.9 2.13§ 2.22§ 0.84 2.4‖ 2.6‖ 2.7‖ 0.96 3.22¶ 1.44¶ 2.2§ 3.0§ 2.9§ 0.9 1.18 1.56 2.26 0.72 1.35 0.69 2.99 2.1§ 0.3 (continued)

Clinical Therapeutics

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Table II. Phase 3 clinical trials with dapagliflozin.

] 2015

DAPA ¼ dapagliflozin; FDA ¼ Food and Drug Administration; FPG ¼ fasting plasma glucose; GLIM ¼ glimepiride; GLIP ¼ glipizide; HbA1c ¼ glycosylated hemoglobin; INS ¼ insulin; MET ¼ metformin; NR ¼ not reported; PBO ¼ placebo; PIO ¼ pioglitazone; SITA ¼ sitagliptin. * Average age of all treatment groups. † FDA-approved dosage of dapagliflozin ¼ 5 mg, 10 mg. ‡ P o 0.001 versus placebo. § P o 0.0001 versus placebo. ‖ P o 0.01. ¶ Data reported as compilation of doses; most patients were receiving maximum dose. P ¼ 0.0007.

0.96‡ 1.00‡ 1.61‡ 0.82 12‡ 20‡ 20‡ NR 0.79‡ 0.89‡ 0.96‡ 0.39 DAPA 2.5 mg DAPA 5 mg DAPA 10 mg PBO INS ⫾ MET 24 59.3 Wilding et al47 (N ¼ 800)

8.55

Age (y)* Study

Table II. (continued).

Baseline HbA1c (%)

Duration (wk)

Background therapy

Treatment groups†

Change in HbA1c (%)

Change in FPG (mg/dL)

Change in weight (kg)

K. Whalen et al. (UTIs) and genital mycotic infections. Few adverse events led to discontinuation of treatment during the trial. The efficacy of canagliflozin as add-on to background therapy with metformin was evaluated in a randomized, double-blind, placebo- and activecontrolled phase 3 study.35 The trial included 1284 patients who were 18 to 80 years of age and had an HbA1c of 7% to 10.5% on a therapeutic dose of metformin. Exclusion criteria were similar to the study by Stenlöf et al33 detailed earlier in this section. Participants were randomized to receive canagliflozin 100 mg, canagliflozin 300 mg, sitagliptin 100 mg (active control), or placebo daily for 26 weeks (period I). At the end of period I, patients in the placebo group were switched to the sitagliptin arm (other patients maintained current treatments), and the study was continued for an additional 26 weeks. The primary outcome measure was the change in HbA1c from baseline at week 26. Secondary outcomes at week 26 included the percentage of patients who achieved an HbA1c o7% and changes in FPG, weight, and systolic blood pressure. The change in HbA1c at week 52 was another secondary end point. Significant reductions in HbA1c at week 26 were observed for both canagliflozin 100 mg (0.79%) and canagliflozin 300 mg (0.94%) compared with placebo (P o 0.001) with metformin background therapy. The percentage of patients who achieved an HbA1c of o7% was 29.8% with placebo, 45.5% with canagliflozin 100 mg, and 57.8% with canagliflozin 300 mg (P o 0.001 for both canagliflozin arms). Reductions in FPG (27 to 38 mg/dL), weight (3.7% to 4.2%), and systolic blood pressure (3.8 to 5.1 mm Hg) were also significant (P o 0.001). At week 52, canagliflozin 300 mg lowered HbA1c by 0.88%, compared with 0.73% with both canagliflozin 100 mg and sitagliptin 100 mg. Genital mycotic infections and adverse events related to osmotic diuresis (eg, polyuria and pollakiuria [increased urinary frequency]) were more common in the canagliflozin treatment groups. The incidence of hypoglycemia was low, but slightly higher with canagliflozin (6.8%) compared with patients who received sitagliptin (4.1%) or placebo/sitagliptin (2.7%). In addition, canagliflozin was examined as add-on therapy to a variety of background treatments, including sulfonylureas,56 metformin/sulfonylurea combination therapy,37,38 metformin/pioglitazone

7

Age (y)

Baseline HbA1c (%)

59.5

8

4

Ferrannini et al49 (N ¼ 408)

58

7.9

12

None

Kadowaki et al50 (N ¼ 547)

57.5

7.95

12

None

Rosenstock et al51 (N ¼ 495)

56–60

7.8–8.1

12

MET

Häring et al52 (N ¼ 669)

57.1

8.1

24

MET þ SU

Kovacs et al53 (N ¼ 499)

54.5

8.1

24

PIO ⫾ MET

Rosenstock et al54 (N ¼ 563)

56.7

8.3

52

MDI insulin ⫾ MET

59

7.89–8.15

78

None

Study Kanada et al48 (N ¼ 100)

Volume ] Number ]

Ferrannini et al55,¶ Study 1 (N ¼ 271)

Duration (wk)

Background therapy Not provided

Treatment groups* EMPA EMPA EMPA EMPA PBO EMPA EMPA EMPA PBO EMPA EMPA EMPA EMPA PBO EMPA EMPA EMPA EMPA EMPA PBO EMPA EMPA PBO EMPA EMPA PBO EMPA EMPA PBO

1 mg 5 mg 10 mg 25 mg 5 mg 10 mg 25 mg 5 mg 10 mg 25 mg 50 mg 1 mg 5 mg 10 mg 25 mg 50 mg 10 mg 25 mg 10 mg 25 mg 10 mg 25 mg

EMPA 10 mg EMPA 25 mg MET

Change in HbA1c (%)

Change in FPG (mg/dL)

0.66 0.72‡ 0.85† 0.82† 0.42 0.4§ 0.5§ 0.6§ þ0.1 0.42‖ 0.40‖ 0.65‖ 0.61‖ þ0.3 0.09 0.23‖ 0.56§ 0.70§ 0.49§ þ0.15 0.82‖ 0.77‖ 0.17‖ 0.59‖ 0.72‖ 0.11 1.18‖ 1.27‖ 0.81

28.1† 35.3§ 41.6§ 42.7§ 15.5 23.2§ 28.9§ 31.0§ þ0.72 22.65‖ 25.28‖ 33.7‖ 32.54‖ þ4.06 2.0 16.0§ 22.0§ 27.0§ 28.0§ þ5.0 23.22 23.22 5.58 16.92‖ 21.96‖ þ6.48 23.76‖ 25.74‖ 11.34

2.5‖ 2.6‖ 2.9‖ 3.1‖ 0.9 1.6‖ 2.3‖ 2.7‖ 2.6‖ 2.9§ 1.2 2.16‖ 2.39‖ 0.39 1.62‖ 1.47‖ þ0.34 1.95‖ 2.04‖ þ0.44

0.34 0.47 0.56

30 28 26

2.2 2.6 1.3

Change in weight (kg) NP

1.81‖ 2.33§ 2.03§

(continued)

Clinical Therapeutics

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Table III. Clinical trials with empagliflozin.

7.88–8.03 60 Study 2 (N ¼ 388)

EMPA ¼ empagliflozin; FDA ¼ Food and Drug Administration; FPG ¼ fasting plasma glucose; HbA1c ¼ glycosylated hemoglobin; MDI ¼ multiple daily injections; MET ¼ metformin; NP ¼ not published; PBO ¼ placebo; PIO ¼ pioglitazone; SITA ¼ sitagliptin; SU ¼ sulfonylurea. * FDA-approved dosage of empagliflozin ¼ 10 mg, 25 mg. † P o 0.01 versus placebo. ‡ P o 0.05 compared to placebo. § P o 0.0001 versus placebo. ‖ P o 0.001 versus placebo. ¶ 78-week open-label extension of two 12-week studies: study 1, continuation of empagliflozin 10 mg, empagliflozin 25 mg, or metformin monotherapy; study 2, continuation of background metformin therapy with empagliflozin 10 mg, empagliflozin 25 mg, or sitagliptin 100 mg.

3.1 4.0 0.4 21 32 16 MET

EMPA 10 mg EMPA 25 mg SITA

0.34 0.63 0.40

Change in weight (kg)

] 2015

Study

Table III. (continued).

Age (y)

Baseline HbA1c (%)

Duration (wk)

Background therapy

Treatment groups*

Change in HbA1c (%)

Change in FPG (mg/dL)

K. Whalen et al. combination therapy,39 and insulin therapy (with or without other antihyperglycemic agents).57 In each case, significant reductions in HbA1c, FPG, and weight were seen when canagliflozin was used as add-on therapy. Compared with an active control as add-on therapy (eg, sitagliptin or glimepiride), canagliflozin demonstrated noninferiority in lowering HbA1c.36,38 Positive effects on weight and systolic blood pressure were noted, similar to the above-mentioned trials.

Dapagliflozin Clinical Trials Ferrannini et al40 evaluated the safety profile and efficacy of dapagliflozin in treatment-naive patients with T2DM. Patients inadequately controlled on diet and exercise alone were randomly assigned in this 24-week, double-bind, parallel-group, placebo-controlled study. Patients, aged 18 to 77 years, were enrolled at 85 sites in the United States, Canada, Mexico, and Russia. Patients were eligible if they had a body mass index (BMI; calculated as weight divided by height squared; kg/m2) r45 and fasting C-peptide Z1.0 ng/mL. History of T1DM, significant renal or hepatic impairment, a CV event (including New York Heart Association Class III/IV heart failure) within the past 6 months, and severe uncontrolled hypertension (systolic blood pressure Z180 mm Hg and/or diastolic blood pressure Z110 mm Hg) excluded patients from entering the study. The study design involved 3 cohorts. Patients with an HbA1c of 7% to 10% were randomly assigned to receive placebo or dapagliflozin 2.5 mg, 5 mg, or 10 mg once daily in the morning (main cohort) or once daily in the evening (exploratory cohort). A third cohort (high HbA1c exploratory cohort) included patients with an HbA1c between 10.1% and 12%. These patients were assigned to 5 mg or 10 mg once daily in the morning. No placebo arm was used secondary to the elevated HbA1c levels. Patients were allowed a rescue medication (metformin) when FPG was 4270 mg/dL at week 4, 4240 mg/dL at week 8, or 4200 mg/dL at weeks 12 to 24. The primary outcome was change in HbA1c from baseline in the main cohort. Secondary end points included changes from baseline in FPG and total weight. In total, 485 patients were randomly assigned to the main and exploratory cohorts, whereas 74 patients were assigned to the high HbA1c exploratory cohort. HbA1c reductions were apparent by week 4 and maintained throughout the trial. The main cohort

9

Clinical Therapeutics saw mean HbA1c reductions from 0.58% to 0.89% with dapagliflozin treatment compared with 0.23% with placebo. The dose-ordered reductions in HbA1c afforded by dapagliflozin were statistically significant for the 5- and 10-mg groups (P ¼ 0.005, P o 0.001, respectively). Patients in the high HbA1c exploratory cohort (10.1%–12%) saw the greatest reduction in HbA1c (1.90% to 1.98%); the P value was not reported. Dapagliflozin was tolerated well and was not discontinued in the study secondary to hypoglycemia. Reductions were statistically significant for FPG in the 5- and 10-mg arms. Reductions in weight and both systolic and diastolic blood pressures were observed but did not reach statistical significance. Significant changes in serum electrolytes or renal function were not observed in the active treatment. Consistent with other SGLT2 inhibitors, patients in the treatment arm experienced more events suggestive of genital infections and UTIs (7.7%–12.9% vs 1.3% placebo and 4.6%–12.5% vs 4% placebo, respectively). Of note, weight reductions did not plateau by the end of the study. Long-term studies may identify a greater weight reduction. Results of other monotherapy trials found similar reductions in HbA1c, weight, and FPG and are summarized in Table II.40–42 The safety profile and efficacy of dapagliflozin was evaluated in a 48-week placebo-controlled, multicenter trial in patients inadequately controlled on insulin (with or without other oral antidiabetic agents).47 A total of 808 patients with T2DM inadequately controlled on at least 30 units of insulin daily were randomly assigned to treatment with dapagliflozin 2.5 mg, 5 mg, 10 mg or placebo. Enrolled patients were between 18 and 80 years of age, had a BMI r45, and an HbA1c between 7.5% and 10.5%. During the 8 weeks before enrollment, patients must have been on at least 1500 mg of metformin daily or at least onehalf the maximum dose of other oral antidiabetic agents. Exclusion criteria included T1DM, eGFR o50 mL/min/1.73 m2, serum creatinine (SCr) 42 mg/dL, or SCr Z1.5 mg/dL for men or Z1.4 mg/dL for women if on metformin. Study medications and oral antidiabetic drugs were not modified except when hypoglycemia was a concern, and the dose of the oral antidiabetic drugs were subsequently decreased. Up titration of insulin was allowed if FPG was 4240 mg/dL between weeks 0 and 12, 4220 mg/dL between weeks 12 and 24, or 4180 mg/dL between weeks 25 and 48

10

with 3 self-reported readings. The primary end point was change in HbA1c from baseline. Secondary outcomes included change in mean insulin dose, weight, and FPG. A statistically significant reduction in HbA1c from baseline was observed (0.32%, 0.49%, 0.54%; P o 0.001 all groups) in the 2.5-, 5-, and 10-mg groups, respectively. The most rapid decrease in HbA1c occurred within the first 8 weeks and was maintained at 48 weeks. Total weight decreased in all groups (0.96 to 1.61 kg), compared with an increase in the placebo arm (0.82 kg). FPG was reduced in all treatment arms. Patients in the dapagliflozin treatment arms did not necessitate an increase in insulin requirement throughout the trial; however, the placebo group requirements did increase progressively (with an up titration mean of 10.54 units/d). Reductions of systolic blood pressure (3.8 to 5.4 mm Hg) along with diastolic reductions (2.3 to 3.1 mm Hg) were noted in the dapagliflozin treatment groups. Orthostatic hypotension was not observed in the treatment arms. Similar to other clinical trials, dapagliflozin was well tolerated, and the overall adverse event rate was similar between the treatment arms. A larger number of patients experienced hypoglycemia in the dapagliflozin arms (56.6%) compared with placebo (51.8%). In addition, more patients in the treatment arms experienced UTIs and genital infections. Data suggest treatment with dapagliflozin improves glycemic control, produces sustained weight loss, and appears to be insulin sparing. Consistently, dapagliflozin 5 and 10 mg daily, improved glycemic control in patients with inadequately controlled T2DM as monotherapy and as add-on combination therapy with metformin,44 glimepiride,17 pioglitazone,45 sitagliptin,46 and insulin47 (Table II). In each trial, significant reductions were noted in HbA1c and FPG. Combination trials saw greater reductions in weight compared with placebo, with similar trends observed in monotherapy trials. In addition, dapagliflozin established noninferiority compared with glipizide in patients inadequately controlled on 1500 to 2500 mg/d metformin.43 Results of this 1-year study found no treatment differences for markers of glycemic control and found a more favorable effect on weight in the dapagliflozin arm. Consistent with the above-mentioned trials, reductions in both systolic and blood pressure were observed.

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Empagliflozin Clinical Trials In a 12-week trial, 408 patients with T2DM were randomized to receive empagliflozin, placebo, or metformin.49 The multicenter trial was conducted at 75 centers in 13 countries. After a 4-week washout period, patients were randomized to receive one of the following: empagliflozin 5 mg, empagliflozin 10 mg, empagliflozin 25 mg, placebo, or open-label metformin at a maximum dose of 1000 mg twice daily. The following patients were included in the study: men and women aged 18 to 79 years with T2DM, treatment-naive for Z10 weeks or on 1 diabetes medication (except TZDs, GLP-1 receptor agonists, or insulin) at a stable dose for Z10 weeks, HbA1c 6.5% to 9% for patients on 1 medication or HbA1c 7% to 10% for treatment-naive patients, and BMI r40. Patients were excluded from the study for the following reasons: acute myocardial infarction, stroke, or transient ischemic attack within the past 6 months; impaired hepatic function; impaired renal function (SCr 41.5 mg/dL for men and 41.4 mg/dL for women); unstable or acute heart failure; acute or chronic acidosis; diseases of the central nervous system, psychiatric disorders, or clinically relevant neurologic disorders; chronic or acute infection; current or chronic urogenital infection; dehydration; history of clinically relevant allergy/hypersensitivity; intolerance to metformin; hereditary galactose intolerance; treatment with TZDs, GLP-1 receptor agonists, or insulin within the past 3 months; use of antiobesity medications; current treatment with systemic steroids; alcohol abuse; treatment with an investigational drug within the past 2 months; and pregnancy, breast-feeding, or not using acceptable birth control methods (women). The primary efficacy end point was the change in HbA1c from baseline to week 12. Secondary end points included change in FPG from baseline to week 12, change in HbA1c from baseline over time, proportion of patients who achieved HbA1c r7% after 12 weeks, proportion of patients who achieved a decrease in HbA1c Z0.5% after 12 weeks, change in weight from baseline to 12 weeks, and pharmacokinetic parameters of empagliflozin. Safety and tolerability were assessed from the following data: incidence and intensity of adverse events, withdrawal from treatment due to adverse events, clinically relevant changes in physical examination, vital signs, electrocardiogram, or laboratory results.

] 2015

Baseline characteristics were similar between groups, and the mean final dose of metformin was 1668 mg/d. Compared with placebo, the mean HbA1c decrease after 12 weeks was greater in all empagliflozin groups (P o 0.0001). In patients with a baseline HbA1c Z8%, the change in HbA1c was 0.6%, 0.7%, and 1.1% in the empagliflozin 5-mg, 10mg, and 25-mg groups, respectively. For patients with a baseline HbA1c of o8%, HbA1c changes of 0.5%, 0.4%, and 0.5% were seen in the empagliflozin 5-mg, 10-mg, and 25-mg groups, respectively. In addition, more patients in the empagliflozin groups achieved an HbA1c r7% and a decrease in HbA1c of Z0.5% compared with placebo. FPG and mean weight decreased in all empagliflozin groups compared with placebo. The incidence of adverse events was similar between all groups, including placebo. The most common adverse events reported with empagliflozin were pollakiuria, thirst, and nasopharyngitis. Seven patients reported adverse events consistent with UTIs, and 5 patients reported adverse events consistent with genital infections. No cases of hypoglycemia occurred in patients who took empagliflozin. No clinically significant changes in physical examination, vital signs, electrocardiogram, or laboratory values were noted. A 12-week study examined the safety profile and efficacy of empagliflozin in 495 patients inadequately controlled on metformin.51 Patients were randomized to receive one of the following regimens in addition to metformin: empagliflozin 1 mg, 5 mg, 10 mg, 25 mg, or 50 mg daily; or placebo; or open-label sitagliptin 100 mg daily. Patients meeting the following criteria were included in the study: age of 18 to 80 years, BMI r40, previous treatment with metformin alone or in combination with 1 additional agent, unchanged diabetes therapy for at least the past 10 weeks, HbA1c 6.5% to 9% for patients on metformin plus 1 additional agent (additional agent was stopped at study entry), or HbA1c 7% to 10% for patients on metformin monotherapy. The exclusion criteria for this study included history of acute myocardial infarction, stroke, or transient ischemic attack in the past 6 months; impaired hepatic or renal function; diseases of the central nervous system; chronic or acute infection; history of allergy/hypersensitivity; and treatment with TZDs, GLP-1 receptor agonists, or insulin within the past 3 months. The primary end point was change in HbA1c from baseline to week 12.

11

Clinical Therapeutics Secondary end points included change in HbA1c over time, change in FPG and weight from baseline to week 12, and proportion of patients achieving HbA1c r7% or HbA1c lowering of Z0.5% at week 12. Assessments for safety and tolerability involved laboratory parameters, vital signs, and adverse event reporting. Of 495 patients randomly assigned, 63% were taking metformin alone and 37% were taking metformin plus 1 additional antidiabetic drug. The placebo-adjusted mean decrease in HbA1c was 0.24%, 0.39%, 0.71%, 0.7%, and 0.64% for the empagliflozin 1-mg, 5-mg, 10-mg, 25-mg, and 50-mg groups, respectively. The changes in HbA1c were statistically significant for all doses except empagliflozin 1 mg daily. More patients in the empagliflozin 10-mg, 25-mg, and 50-mg groups achieved an HbA1c r7% than placebo. FPG and weight were also significantly decreased in patients taking empagliflozin compared with placebo, except in the 1-mg group. The most commonly reported adverse events in patients taking empagliflozin were UTI and pollakiuria. Fourteen patients taking empagliflozin reported symptoms consistent with UTI and genital infections. Hypoglycemia was reported in 4 patients taking empagliflozin; however, no patients experienced a blood glucose level o54 mg/dL. Empagliflozin was also studied in combination with a sulfonylurea,52 pioglitazone (with or without metformin),53 and insulin.54 The results of these studies consistently revealed significant reductions in HbA1c, FPG, and weight. A long-term, active control trial that involved empagliflozin 10 mg or 25 mg as monotherapy or add-on to metformin found empagliflozin provides sustained glycemic control and continued weight loss over 90 weeks with a low risk of hypoglycemia in patients with T2DM.55

CV Safety Profile SGLT2 inhibitors are associated with a reduction in systolic and diastolic blood pressures when used as both monotherapy or in combination with other glucose-lowering agents.58–60 A meta-analysis of 21 placebo-controlled trials indicated a mean drop in systolic blood pressure of 3.77 mm Hg. The same analysis reported a drop of 1.75 mm Hg in diastolic blood pressure across 16 placebo-controlled trials.59 Although the mechanism is not completely understood, these effects are likely attributed to a glucose-induced

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osmotic diuresis. Symptomatic hypotension may occur in patients with an eGFR o60 mL/min/ 1.73 m2, patients on diuretics or medications that interfere with the renin-angiotensin-aldosterone system, the elderly, or patients with low systolic blood pressure.8–10 Small changes in fasting lipid profiles were reported with the SGLT2 inhibitors, including an increase in high-density and low-density lipoproteins and a decrease in triglycerides.15,59 Whether this represents a clinically significant effect remains unknown. Weight loss of
1 to 5 kg was observed in all studies with SGLT2 inhibitors and appears to be sustained at 48 to 52 weeks of follow-up.45 Weight loss is predominately because of loss of fat, particularly visceral adipose tissue, rather than lean mass.58,61 Both monotherapy and combination therapy trials have reported weight reduction that may mitigate weight gain associated with insulin and/or TZDs.45 CANVAS (CANagliflozin cardioVascular Assessment Study) is an ongoing CV safety study of canagliflozin in 4330 persons with CV disease or at high risk. Preliminary results suggest that canagliflozin is not associated with an increased risk of CV events.62 However, an elevated stroke risk was found within the first 30 days of canagliflozin therapy. Final results of CANVAS are not expected until sometime in 2015.63 An updated meta-analysis of dapagliflozin, consistent with previous meta-analyses, found no unacceptable increase in CV risk.64,65 A CV outcome trial with empagliflozin is also currently under way.66

Adverse Events SGLT2 inhibitors did not lead to significant changes in renal function in phase 2 and 3 studies.8–10 Although no significant changes were observed, elevations in SCr and blood urea nitrogen may occur. Patients with hypovolemia are more susceptible and may require more frequent monitoring of renal function.8–10 This class of drugs is primarily renally eliminated, and exposure to these agents is increased in renal impairment. Paradoxically, however, glucose lowering is decreased in severe renal impairment.8–10,58 Because the ability to enhance UGE is diminished with severe renal impairment, the SGLT2 inhibitors are expected to be ineffective in patients with an eGFR o30 mL/min/ 1.73 m2. Promotion of glucosuria with the SGLT2 inhibitors may be anticipated to increase the incidence of

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K. Whalen et al. genitourinary infections (Table IV).15,57,67 The increased incidence (approximately double) of genital infections appears more pronounced in women, although uncircumcised men were also at a higher risk of infection such as balanitis and balanoposthitis. Patients with a prior history of genital mycotic infections were more likely to encounter subsequent mycotic infections.9 The frequency of UTIs was inconsistent among trials but also appeared to be increased.15,58 Genital infections were not dose dependent and led to discontinuation of therapy in o1% of patients. The occurrence of both mycotic infections and UTIs in clinical trials appears to be reduced over time. Discontinuations due to UTIs and genital infections occurred within the first year of treatment, with no discontinuation observed in the second year.61 A small increase in the number of bladder tumors (10 of 6045 patients) was reported in clinical trials with dapagliflozin.65 Five of these cases occurred during the first 6 months of therapy, which may cast doubt on the direct link between the medication and the development of cancer. In addition, baseline hematuria was observed in 9 of the 10 patients. Two of the patients had a history of hematuria before dapagliflozin therapy. In any case, the FDA has proposed continued clinical and statistical surveillance; package labeling includes a warning for bladder cancer in patients with prior or active history of bladder cancer.9,65 Risk factors associated with reported cases include male sex, advanced age, and pioglitazone use.65 Of note, dapagliflozin was not initially approved by the FDA in 2011, secondary to

an increased incidence of bladder cancer. An increase in bladder cancer was not observed with empagliflozin or canagliflozin. However, after-marketing surveillance data is being collected on all of the SGLT2 inhibitors.68

ROLE IN THERAPY On the basis of available data from clinical trials, SGLT2 inhibitors appear to be effective as monotherapy and add-on therapy for patients uncontrolled on metformin, sulfonylureas, insulin, or other antihyperglycemic combinations. The class lowers HbA1c by
0.5% to 1% and is potentially useful for patients with an HbA1c o9%. SGLT2 inhibitors have a unique mechanism of action that promotes weight loss and reductions in blood pressure, with a low risk of hypoglycemia. These agents are well suited for obese or hypertensive patients and patients at risk of hypoglycemia. One caveat, however, would be in combining SGLT2 inhibitors with insulin and sulfonylureas, because hypoglycemia may be more likely to occur. Inhibiting SGLT2 receptors and increasing UGE facilitates the pathogenesis of and may lead to UTIs and genital mycotic infections. Patients with a history of these infections should avoid SGLT2 inhibitors. In addition, patients with postural hypotension and renal impairment are not ideal candidates for these drugs. SGLT2 inhibitors increase lowdensity lipoprotein; whether this is clinically meaningful remains to be determined. Despite proven efficacy, questions are still unanswered, and the exact role of these agents is unclear. In the most recent American Diabetes Association guidelines on the management of hyperglycemia in

Table IV. Common adverse effects with SGLT2 inhibitors.8–10 Canagliflozin* Adverse effect (%) Female genital mycotic infections Male genital mycotic infections Increased urination Urinary tract infections

Dapagliflozin†

Empagliflozin‡

100 mg

300 mg

5 mg

10 mg

10 mg

25 mg

10.4 4.2 5.3 5.9

11.4 3.7 4.6 4.3

8.4 2.8 2.9 5.7

6.9 2.7 3.8 4.3

5.4 3.1 3.4 9.3

6.4 1.6 3.2 7.6

SGLT2 ¼ sodium-glucose co-transporter 2. * Pooled data from 4 placebo-controlled trials that reflect exposure of 1667 patients to canagliflozin. † Pooled data from 12 placebo-controlled trials that reflect exposure of 2338 patients to dapagliflozin. ‡ Pooled data from 5 placebo-controlled trials that reflect exposure of 1976 patients to empagliflozin.

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Clinical Therapeutics T2DM, SGLT2 inhibitors are 1 of 6 treatment options that may be considered as combination therapy with metformin if the HbA1c target is not achieved after 3 months of metformin monotherapy at maximum tolerated doses. In addition, if a patient has an intolerance or contraindication to metformin therapy, SGLT2 inhibitors may be considered as initial drug therapy according to the American Diabetes Association.6 The American Association of Clinical Endocrinologists lists SGLT2 inhibitors as agents that may be used cautiously either as monotherapy or dual/triple combination therapy.69 This is because of the lack of evidence available at the time the American Association of Clinical Endocrinologists guidelines were published in 2013. Expense, adverse events, and lack of long-term efficacy data may limit the use of these agents. Longterm safety end points, including cancer and CV outcomes, need to be explored. Data thus far are reassuring; however, after-marketing studies may help quantify any potential associations with these adverse outcomes. Studies that examine the clinical significance of inhibition of SGLT1 are also under way. In addition, the use of SGLT2 inhibitors in persons with T1DM and children is currently being investigated.15

CONCLUSION The SGLT2 inhibitors represent a new class of antihyperglycemics that improve glucose control by increasing UGE. The mechanism of action renders them effective as monotherapy or add-on therapy in combination with a variety of other medications for diabetes. Added benefits of the SGLT2 inhibitors include a modest reduction in weight and systolic blood pressure and a low risk of hypoglycemia. The decision to use these agents should be based on patient-specific factors such as reduction in HbA1c needed, renal function, tolerability, and cost issues.

ACKNOWLEDGMENT Dr. Miller was primarily responsible for researching and writing the sections pertaining to dapagliflozin. Dr. St. Onge was primarily responsible for preparation of the sections pertaining to empagliflozin. Dr. Whalen was responsible for preparation of the sections pertaining to canagliflozin and for compilation and review of the final manuscript.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.

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Address correspondence to: Karen Whalen, PharmD, BCPS, CDE, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, 1225 Center Drive, HPNP Building, Room 4321, Gainesville, FL 32610. E-mail: [email protected]fl.edu

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