Clinical Review A Review of the Efficacy and Safety of Canagliflozin in Elderly Patients with Type 2 Diabetes Lindsey K. Elmore, Sara Baggett, Jeffrey A. Kyle, Jessica W. Skelley OBJECTIVE: To review the efficacy and safety of canagliflozin (CAN) in elderly patients with type 2 diabetes mellitus (T2DM). DATA SOURCES: Studies were identified using PubMed, International Pharmaceutical Abstracts, MEDLINE, Academic Search Premier, SCOPUS, and Google Scholar from 2011 to August 2013. The following key words were reviewed: canagliflozin, canagliflozin elderly, canagliflozin geriatrics, dapagliflozin, sodium glucose cotransporter 2 (SGLT2) inhibitors, and SGLT2 receptor inhibitors. DATA EXTRACTION: Articles evaluating CAN for diabetes that were published in English and used human subjects were selected. Fifteen clinical trials were identified and evaluated. STUDY SELECTION: Of 15 identified articles, 2 articles, 2 published posters, and unpublished information from the manufacturer were chosen based on the mean age of the study subjects. DATA SYNTHESIS: Evidence that elderly patients with T2DM have less A1C reduction with CAN is presented; the benefit on A1C is significant. Systolic blood pressure (SBP) and body weight reduction in the elderly were consistent with younger patients. Adverse effects such as increased urinary frequency, genital mycotic infections, and urinary tract infections may discourage the use of CAN in the elderly patient. CONCLUSION: Treatment with CAN improves A1C levels, reduces SBP and body weight, and is overall well tolerated in older subjects with T2DM. Risks and benefits of treatment with CAN should be assessed in geriatric patients on a case-by-case basis. Safety in elderly patients was consistent with that of other phase 3 trials in the general population. Additional longterm cardiovascular studies are needed.

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KEY WORDS: Canagliflozin, Diabetes, Elderly, Geriatrics, SGLT2

inhibitor, Type 2 diabetes. ABBREVIATIONS: ADE = Adverse drug event, AE = Adverse

effects, AHA = Antihyperglycemic agent, AUC = Area under the curve, BMI = Body mass index, BP = Blood pressure, CAN = Canagliflozin, CKD = Chronic kidney disease, CV = Cardiovascular, DBP = Diastolic blood pressure, eGFR = Estimated glomerular filtration rate, FPG = Fasting plasma glucose, HDL-C = High-density lipoprotein cholesterol, ITT = Intention-to-treat, LDL-C = Low-density lipoprotein cholesterol, SBP = Systolic blood pressure, SGLT2 = Sodium glucose cotransporter 2, SU = Sulfonylurea, T2DM = Type 2 diabetes mellitus, UGT = UDPglucuronosyl transferase, UTI = Urinary tract infection. Consult Pharm 2014;29:335-46.

Introduction According to the 2011 National Diabetes Fact Sheet, 25.8 million people are affected by diabetes in the United States. Of those, 10.9 million are 65 years of age and older.1 The appropriate target for A1C in fit elderly patients should be similar to the target A1C of younger adults (< 7.0%).2,3 In older patients with cognitive or functional disability and limited life expectancy, glycemic goals may be less stringent.2 Special considerations for older adults also need to be placed on the increased prevalence of coexisting illnesses such as hypertension, congestive heart disease, stroke, and the relative inability of older patients with type 2 diabetes mellitus (T2DM) to tolerate the adverse effects (AEs) of medications.3 The risk of treatment-associated hypoglycemia and AEs are heightened by various factors including polypharmacy, chronic renal and hepatic impairment, and multiple comorbidities, more common in older patients with T2DM than in younger patients.4 When selecting antihyperglycemic agents (AHAs) for older adults with T2DM, safety concerns such as renal function, drugdrug interactions, heart disease, urinary incontinence, and potential for injurious falls should be considered.4 Consensus guidelines for the treatment of T2DM in the elderly suggest that metformin and dipeptidyl peptidase-4 inhibitor are attractive therapy options for use because of their low propensity to cause hypoglycemia and weight gain, and metformin is considered the drug of

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Clinical Review choice for the treatment of hyperglycemia in the elderly. Other classes of medications are less highly favored for a variety of reasons. Sulfonylureas (SUs) and insulin are less-attractive options because of hypoglycemia; thiazolidinediones because of weight gain, fracture, and bladder cancer risk; and α-glucosidase inhibitors because of cost and gastrointestinal intolerance. Insulin may be required; however, patients should be carefully selected to avoid hypoglycemia, and doses should be initially low and titrated slowly.3 Alternative agents with a low propensity to cause weight gain, hypoglycemia, fractures, and other AEs may expand the options for the treatment of diabetes in elderly patients. On March 29, 2013, the Food and Drug Administration approved canagliflozin (CAN) (Invokana, Janssen Pharmaceuticals) as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. It is currently the first and only sodium-glucose cotransporter 2 (SGLT2) inhibitor in the United States.5 The kidneys reabsorb glucose primarily via the transporter protein SGLT2 located in the proximal renal tubule of the nephron.6 The SGLT2 protein is increased in patients with T2DM, which can lead to increased glucose reuptake and a higher level of circulating glucose in the bloodstream.6 By directly inhibiting SGLT2, CAN lowers the renal threshold for glucose and reduces reabsorption of filtered glucose, thereby increasing urinary glucose excretion and reducing serum levels (Figure 1).7 The purpose of this paper is to review the clinical efficacy and safety of CAN, specifically for the treatment of elderly patients with T2DM.

Data Extraction Studies were identified by searching PubMed, International Pharmaceutical Abstracts, MEDLINE, Academic Search Premier, SCOPUS, and Google Scholar from January 2011 to August 2013 using key words: canagliflozin, canagliflozin in the elderly, canagliflozin in geriatrics, dapagliflozin, SGLT2 inhibitors, and SGLT2 receptor inhibitors. Clinical trials evaluating CAN for diabetes that were published in English and used human subjects were selected. A total of 15 clinical trials were identified. For the purposes of this review, two articles, two published posters,

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and unpublished information from the manufacturer were chosen. These articles were chosen because the mean age of the study subjects best represented the American Diabetes Association and American Geriatrics Society consensus definition of older adults, which is patients 65 years of age and older. References cited in the articles were used to identify additional citations.

Clinical Trials Table 1 provides a summary of all clinical trials included in this review. Bode et al. performed a 26-week, doubleblind, placebo-controlled, phase 3 study that evaluated the efficacy and safety of CAN in older adults 55 to 80 years of age with T2DM.4 Patients with poorly controlled T2DM (A1C ≥ 7% and ≤ 10%) who were currently receiving treatment for diabetes (either diet and exercise alone or in combination with oral or parenteral agents) were randomized to CAN 100 mg, 300 mg, or placebo daily. The primary endpoint was change in A1C level at week 26. Secondary endpoints included proportion of subjects achieving A1C of < 7%, change in fasting plasma glucose (FPG), percentage change in body weight, change in systolic blood pressure (SBP), and change in fasting highdensity lipoprotein cholesterol (HDL-C) and triglycerides.4 A total of 714 patients with a mean age of 63.6 years, A1C of 7.7%, duration of T2DM of 11.7 years, body mass index (BMI) of 31.6 kg/m2, and estimated glomerular filtration rate (eGFR) of 77 mL/min/1.73 m2 received at least one dose of study medication and were analyzed with a modified intention-to-treat (ITT) method. Fifty-five percent of patients were male, 77.3% were white. Of note, 38.2% of participants were 65 years of age and older, and 6.4% were 75 years of age and older. Most patients were on background antihyperglycemics, with metformin, SUs, and insulin being the most common.4 At the study’s end, CAN significantly lowered A1C from baseline placebo (0.57% for 100 mg, and 0.70% for 300 mg versus 0.03% in placebo; P < 0.001 for both doses). More patients achieved A1C < 7.0% with both CAN doses versus placebo (47.7% in 100 mg group, and 58.5 % in 300 mg group versus 28.0% in placebo group; P < 0.001 for both measures). FPG level was also reduced compared

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Figure 1. Mechanism of Action for Canagliflozin

Sodium-glucose co-transporter 2 (SGLT2) is expressed in the proximal renal tubules, and is responsible for reabsorption of filtered glucose from the tubular lumen. Canagliflozin (CAN) is an inhibitor of SGLT2 that reduces reabsorption of filtered glucose, thereby reducing the amount of glucose available for transport back into the blood via the GLUT2 transporter, and increasing urinary glucose excretion.

Abbreviations: ATPase = Sodium-potassium adenosine triphosphatase, CAN = Canagliflozin, GLUT2 = Glucose transporter 2, K+ = Potassium ion, Na+ = Sodium ion. Source: References 11, 18.

with placebo (-18.1 mg/dL in 100 mg group, -20.3 mg/dL in 300 mg group, versus +7.4 mg/dL in placebo group; P < 0.001 for both comparisons). Patients taking CAN 100 mg had a mean reduction in body weight of -2.3% (-2.1 kg), and patients on CAN 300 mg had a reduction of -3.0%, (-2.7 kg), versus -0.01% (0.1 kg) in placebo group (P < 0.001 for both CAN doses). Mean lowering of SBP in patients taking the 100 mg and 300 mg dose was -3.5 mmHg and -6.8 mmHg, respectively, versus a 1.1 mmHg

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increase in patients taking placebo (P < 0.001 for both doses versus placebo). Increases in HDL-C were observed with 100 mg and 300 mg CAN placebo (2.7 mg/dL, 2.2 mg/dL, versus 0.4 mg/dL respectively; P < 0.001 for both doses). Triglycerides were reduced by -4.7 mg/dL in CAN 100 mg group, -2.5 mg/dL in CAN 300 mg group, and -0.3 mg/dL in placebo group (P-value NS for both measures). In subjects older than 65 years of age, modestly greater reductions in A1C levels from baseline to week 26

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Table 1. Clinical Trials on the Safety and Efficacy of Canagliflozin in Elderly Patients Study

Design

Treatment

Bode et al.4

26 wk, MC, DB, R, PCT

N = 714 CAN 300 mg, 100 mg, Age 64 yrs (55-80 yrs), P daily T2DM A1C ≥ 7% and ≤ 10%

Demographics Endpoint

Results

Safety

A1C Genital mycotic 100 mg 0.6% infections 300 mg 0.7% 100 mg P 0.03% (P-value < Men 3.2% 0.001 for both doses) Women 15.4% Secondary: 300 mg Proportion Proportion Men 6.2% of patients 100 mg 47.7% Women 11.2% 300 mg 58.5% achieving P A1C < 7%, P 28% (P-value < Men 0% change in 0.001 for both doses) Women 2.1% FPG, BW, FPG SBP, and Hypotension 100 mg -18.1 mg/dL fasting 100 mg 0.8% 300 mg -20.3 mg/dL HDL-C and 300 mg 0.4% P +7.4 mg/dL (P-value triglycerides P 0% < 0.001 for both doses) Postural dizziness 100 mg 0.8% BW 300 mg 1.3% 100 mg 2.4% P 0.4% 300 mg -3.1% P -0.1% (P-value < Pollakiuria 0.001 for both doses) 100 mg 2.5% 300 mg 5.1% SBP P 2.1% 100 mg -3.5 mmHg 300 mg -6.8 mmHg Polyuria P +1.1 mmHg (P-value 100 mg 1.7% < 0.001 for both 300 mg 1.7% doses) P 0% Primary: Change in A1C at wk 26

HDL-C 100 mg -2.7 mg/dL 300 mg -2.2 mg/dL P 0.4 mg/dL (P-value < 0.001 for both doses) Triglycerides 100 mg - 4.7 mg/dL 300 mg -2.5 mg/dL P -0.3 mg/dL

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Table 1. Clinical Trials on the Safety and Efficacy of Canagliflozin in Elderly Patients (continued) Study

Design

Treatment

Yale et al.7

26 wk, MC, DB, R, PCT

CAN 300 N = 269 mg, 100 mg, Age 68 yrs, P daily T2DM A1C ≥ 7% and ≤ 10.5% CKD III (eGFR ≥ 30 mL/min/1.73 m2)

Demographics Endpoint Primary: Change in A1C at wk 26 Secondary: Proportion of patients achieving A1C < 7%, change in FPG

Results

Safety

A1C 100 mg -0.3% 300 mg -0.44% P -0.03% (P-value < 0.05)

Genital mycotic infections 100 mg Men 1.7% Women 3.1% 300 mg Men 2.1% Women 2.4% P Men 0% Women 0%

Proportion 100 mg 27.3% 300 mg 32.9% P 17.2% (P-value not determined) FPG 100 mg -14.9 mg/dL 300 mg -11.7 mg/dL P 0.5 mg/dL (P-value not determined)

Hypotension 100 mg 0% 300 mg 1.1% P 0% Postural dizziness 100 mg 1.1% 300 mg 2.2% P 0% Pollakiuria 100 mg 2.2% 300 mg 4.5% P 1.1% Polyuria 100 mg 0% 300 mg 0% P 0%

Mathews et al.9

Subgroup of patients in CANVAS trial on ≥ 30 units insulin/day

CAN 300 N = 1718 mg, 100 mg, Age 62.8 yrs, P daily T2DM A1C ≥ 7% and ≤ 10.5%

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Primary: Change in A1C at wk 18 Secondary: Proportion of patients achieving A1C < 7%, change in FPG, BW, SBP, and fasting HDL-C and triglycerides

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A1C Genital mycotic 100 mg -0.63% infections 300 mg -0.72% 100 mg P +0.01% (P-value < Men 4% 0.001 for both doses) Women 11.8% 300 mg Proportion Men 8.3% 100 mg 19.8% Women 9.9% 300 mg 24.7% P P 7.7% (P-value < Men 0.5% 0.001 for both doses) Women 2.2% Hypotension 100 mg 0% 300 mg 0.7% P 0% 339

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Table 1. Clinical Trials on the Safety and Efficacy of Canagliflozin in Elderly Patients (continued) Study

Design

Treatment

Demographics Endpoint

Mathews et al.9

Results

Safety

FPG 100 mg -18 mg/dL 300 mg -25.2 mg/dL P +3.6 mg/dL (P-value < 0.001 for both doses)

Postural dizziness 100 mg 0.2% 300 mg 1.2% P 0% Pollakiuria 100 mg 3.7% 300 mg 5.6% P 0.5%

BW 100 mg -1.8% 300 mg -2.3% Polyuria P 0.1% (P-value < 100 mg 1.1% 0.001 for both doses) 300 mg 0.7% SBP P 0.4% 100 mg -5.1 mmHg 300 mg -6.9 mmHg P -2.5 mmHg (P-value < 0.001 for both doses) HDL-C 100 mg -9.27 mg/dL 300 mg -19.44 mg/dL P 3.24 mg/dL (P-value < 0.001 for 300 mg dose, NS for 100 mg) Triglycerides 100 mg -3.24 mg/dL 300 mg -12.96 mg/dL P -9.72 mg/dL (P-value NS for both doses) Fulcher et al.10

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Subgroup of patients in CANVAS trial on sulfonylureas

N = 127 CAN 300 mg, 100 mg, N = 1,718 Age 64.8 yrs, P daily T2DM A1C ≥ 7% and ≤ 10.5%

Primary: Change in A1C at wk 18

A1C 100 mg -0.7% 300 mg -0.79% P +0.04% (P-value < 0.001 for both doses)

Derived from different patient population and therefore not reported

Proportion 100 mg 25% 300 mg 33.3% P 5% (P-value < 0.01 for both doses)

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Table 1. Clinical Trials on the Safety and Efficacy of Canagliflozin in Elderly Patients (continued) Study

Design

Treatment

Demographics Endpoint

Fulcher et al.10

Secondary: Proportion of patients achieving A1C < 7%, change in FPG, BW, SBP, and fasting HDL-C and triglycerides

Results

Safety

FPG 100 mg -25.4 mg/dL 300 mg -36.1 mg/dL P +12 mg/dL (P-value < 0.001 for both doses) BW 100 mg -0.6% 300 mg -2% P -0.2% (P-value < 0.025 for 300 mg and NS for 100 mg) SBP 100 mg -3.5 mmHg 300 mg -5.2 mmHg P -3.4 mmHg (P-value NS for both doses) HDL-C 100 mg 4.2 mg/dL 300 mg 3.3 mg/dL P 3.2 mg/dL (P-value NS for both doses) Triglycerides 100 mg -30.3 mg/dL 300 mg +6.2 mg/dL P -3.8 mg/dL (P-value NS for both doses)

Abbreviations: BW = Body weight, CAN = Canagliflozin, DB = Double blind, FPG = Fasting plasma glucose, HDL-C = High-density lipoprotein cholesterol, MC = Multi-center, P = Placebo, PCT = Placebo-controlled trial, R = Randomized, SBP = Systolic blood pressure, T2DM = Type 2 diabetes mellitus. Source: References 4, 7, 9, 10.

were observed (placebo-subtracted mean changes of -0.65% and -0.82%, respectively) in subjects 65 years of age or older (placebo-subtracted mean changes of -0.45% and -0.50%, respectively). The most common AEs were genital mycotic infection, urinary tract infection (UTI), and pollakiuria (defined as frequent urination. Does not include polyuria, i.e., urinating large volumes).4

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Yale et al. evaluated the efficacy and safety of CAN 100 mg and 300 mg in subjects with chronic kidney disease (CKD) in a randomized, double-blind, placebo-controlled trial. Patients were recruited from 89 centers in 19 countries and were eligible for the trial if they were 25 years of age or older, had an A1C ≥ 7.0% and ≤ 10.5%, and stable stage 3 CKD (eGFR ≥ 30 mL/min/1.73 m2). Patients were permitted to be on any stable AHA regimen, or no AHA regimen at

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Clinical Review all. Patients were excluded if they had FPG > 270 mg/dL, a history of type 1 diabetes mellitus, need for dialysis, renal disease requiring immunosuppression, nephrotic syndrome, inflammatory renal disease, Class III-IV heart failure, and others. The prespecified primary efficacy endpoint was the change from baseline in A1C at week 26. Prespecified secondary efficacy endpoints evaluated at week 26 were the proportion of subjects reaching A1C < 7.0% and change from baseline in FPG.7 Of the 714 patients, 269 were analyzed with a modified ITT analysis. The mean age of subjects was 68 years, 60.6% were male, 79.9% were white, baseline eGFR was 39 mL/min/1.73 m2, mean A1C was 8.0%, and mean BMI was 33 kg/m2. Ninety-eight percent of patients were on background AHAs, with insulin and SUs being most common, and 80% of patients had at least one microvascular complication of T2DM.7 A1C was significantly reduced with both CAN 100 mg and CAN 300 mg relative to placebo (-0.30%, -0.44%, and -0.03%, respectively; P < 0.05). A higher proportion of subjects on CAN 100 mg and 300 mg achieved an A1C < 7.0%, with CAN 100 mg and 300 mg versus placebo (27.3%, 32.9% and 17.2%, respectively; P-value not determined because of the multiplicity of control). Change in FPG was not statistically significant for 300 mg placebo, and P-value was not determined for 100 mg because of multiplicity control (Least squared [LS] mean change -14.94 mg/dL in CAN 100 mg, -11.7 mg/dL in CAN 300 mg, and -0.54 mg/dL in placebo).7 The Phase 3 CAN Cardiovascular Assessment Study (CANVAS) is an ongoing study comparing CAN with placebo in subjects with T2DM on a wide range of antihyperglycemic agents and a history or high risk of cardiovascular (CV) disease.9,10 Patients were included if they were 30 years of age or older, had a history or an increased risk of CV disease (defined as 30 years of age or older with symptomatic atherosclerotic disease, or 50 years of age or older, with two or more risk factors), had an A1C ≥ 7.0% and ≤ 10.5%, and could be on any AHA therapy or no therapy. Primary study endpoints included change in A1C from baseline to 18 weeks, and secondary endpoints included change in FPG, SBP, proportion of patients

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achieving A1C < 7%, and percent change in body weight, triglycerides, and HDL. Endpoints were analyzed using a modified ITT analysis of patients who received at least one dose of study medication. Two prespecified, subgroup analyses were published via poster presentation. Matthews et al. evaluated CAN in combination with insulin, and Fulcher et al. evaluated CAN in combination with SUs.9,10 Matthews et al. evaluated the efficacy and safety of CAN in patients on 30 units/day or more of insulin therapy at study entry. In total, 1,718 subjects were randomized in the subgroup to receive CAN 100 mg or 300 mg or placebo once daily over 18 weeks. Patients were well matched in each group, with an average age of 62.8 years, 67% male, 78% white, mean BMI of 33.8, and a mean eGFR of 74.9 mL/min/1.73 m2; average daily insulin dose at baseline of 83 units per day, average duration of T2DM of 16.6 years, and average duration of continuous insulin therapy of 7.1 years; the majority of subjects received both basal and bolus insulin.9 At week 18, CAN 100 mg and 300 mg provided significant reductions in A1C levels placebo (LS mean changes placebo were -0.63% and -0.72%, respectively versus +0.01% in placebo group [P < 0.001 for both measures]). A higher proportion of subjects treated with CAN 100 and 300 mg achieved HbA1c < 7.0% than with placebo (19.8%, 24.7%, and 7.7%, respectively; P < 0.001 for both CAN doses). CAN also produced significant reductions in SBP, but not diastolic blood pressure (DBP). SBP was lowered -5.1 mmHg in the 100 mg group, -6.9 mmHg in the 300 mg group, and -2.5 mmHg in the placebo group; P < 0.001 for both doses versus placebo. Both doses reduced body weight from baseline compared with placebo, with LS mean percent change for the 100 mg and 300 mg dose of -1.8% (-1.8 kg) and -2.3% (-2.3 kg), respectively, versus 0.1% in the placebo group (P < 0.001 for both doses). CAN 300 mg increased HDL-C levels versus placebo, but not 100 mg (LS mean change of 0.54 mg/dL in 100 mg group, 1.08 mg/dL in 300 mg group, and 0.18 mg/dL in placebo group; P < 0.001 for 300 mg dose, not significant for 100 mg dose), and there was no difference in triglycerides. FPG decreased by 18 mg/dL in 100 mg group, 25.2 mg/dL in 300 mg group, and 3.6 mg/dL in placebo

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group (P-value < 0.001 for both measures). Female genital mycotic infections and pollakiuria were the most common side effects, and there were minimal changes in laboratory measures of liver and kidney function.9 In another prespecified subgroup analysis, Fulcher et al. evaluated the efficacy and safety of CAN in subjects with T2DM inadequately controlled on SU monotherapy. A total of 127 subjects on protocol-specific doses of SU monotherapy at study entry were randomized to CAN 100 mg, 300 mg, or placebo once daily. Primary endpoint was the change in A1C at 18 weeks, and secondary endpoints were proportion of subjects reaching A1C < 7.0%, change in FPG, SBP, body weight, HDL-C, and triglycerides. Patients had a mean age of 64.8 years, and baseline SU therapies were glimepiride (35%), glyburide/glibenclamide (29%), and gliclazide MR (27%).10 Both CAN doses significantly improved A1C compared with placebo at week 18 (100 mg -0.70%, 300 mg -0.79, versus 0.04% in placebo; P < 0.001 for each dose). A higher proportion of patients treated with CAN 100 mg and 300 mg achieved A1C < 7.0% versus placebo (25.0%, 33.3%, and 5.0%, respectively; P < 0.01). Significant differences in FPG levels (-48.1 mg/dL; P < 0.001) and body weight (-1.8 kg; P < 0.025) were seen with CAN 300 mg compared with placebo. Numerical decreases were noted in change in SBP, DBP in CAN 100 mg, 300 mg and placebo groups, and numerical increases in triglycerides, low-density lipoprotein cholesterol (LDL-C), and nonHDL-C levels were seen in the 300 mg dose and placebo. Safety endpoints were measured in a separate population, and are therefore not reported here.10 Unpublished information from the package insert states that there have been 2,034 patients 65 years of age and older, and 345 patients 75 years of age and older exposed to CAN in a total of nine clinical studies. A1C lowering with CAN relative to placebo was lessened in patients 65 years of age and older (-0.61% with CAN 100 mg and -0.74% with CAN 300 mg versus placebo) compared with younger patients (-0.72% with CAN 100 mg and -0.87% with CAN 300 mg versus placebo).11

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Dosage and Administration CAN is available as an oral tablet in two strengths: 100 mg and 300 mg. A daily dose of 100 mg/day is initially recommended; however, the dose may be increased to 300 mg/ day if additional glycemic control is needed.11 Since CAN reduces postprandial glucose excursions because of the delay in intestinal glucose absorption, it is recommended to administer CAN prior to the first meal of the day.11 For patients with renal impairment CAN doses should be adjusted. In patients with moderate renal impairment (eGFR ≥ 45 to < 60 mL/min/1.73 m2), the dose should be limited to 100 mg once daily. CAN should be avoided in patients with an eGFR of < 45 mL/min/1.73 m2.11 In patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or receiving dialysis, CAN is not expected to be effective.11 No dosage adjustments are necessary for patients with mild to moderate hepatic impairment (Child-Pugh class A or B). CAN should not be used in those with severe hepatic impairment (Child-Pugh class C).11 Patients who are concomitantly taking an UDPglucuronosyl transferase (UGT) enzyme inducer such as phenytoin or rifampin and whose eGFR of ≥ 60 may need to increase the dose of CAN to 300 mg daily. However, in patients who have an eGFR of ≥ 45 to < 60 mL/min/1.73 m2, an alternative antihyperglycemic agent may need to be selected. Tablets should be stored at room temperature (25oC), with an acceptable range of 15°C-30°C.11

Adverse Effects In trials analyzed, the incidence of any AE ranged from 54.1% to 78% in CAN 300 mg group, 39.2% to 78.9% in CAN 100 mg group, and 56.5% to 74.4% in the placebo group.4,7,9 Patients 65 years of age and older also had a higher incidence of AEs related to reduced intravascular volume including hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration, particularly with the 300 mg daily dose compared with younger patients. There was a more prominent increase in the incidence of AEs in patients who were 75 years of age and older.11

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The most common AEs were osmotic diuresis, genital mycotic infections, and depleted intravascular volume. Hypoglycemia was rare, and most commonly occurred in combinations with SUs and insulin. Pollakiuria and polyuria were more frequent with CAN compared with placebo, and ranged from 4.2% to 5.6% in trials reviewed.4,7,10 CAN increased the incidence of genital mycotic infections, especially in women compared with men (2.4%-11.2% and 0.0%-8.3%, respectively).4,7,9,10 Postural dizziness and hypotension were variable in patients taking CAN 100 mg and 300 mg (incidence range 0.0%-2.2%) in studies reviewed. Patients ≥ 75 years of age, with moderate renal impairment (eGFR ≥ 30 and ≤ 60 mL/min/1.73 m2), and/or who take loop diuretics, are at an increased risk of ADEs related to intravascular volume depletion.11 Incidence of hypoglycemia is rare when CAN is taken as monotherapy (3%-3.6% versus 2.6% in placebo), and risk is increased in patients on AHA, especially insulin (48.6%-49.3% versus 38.6% in placebo) and SU agents (4.1%-12.5% versus 5.8% in placebo).11 ADEs were generally reported as mild to moderate in intensity, and resulted in few study discontinuations, but discontinuations that did occur were determined be related to study medication.

Drug Interactions O-glucuronidation via UGT1A9 and UGT2B4 is the major metabolic elimination pathway for CAN. Concomitant use with rifampin, a nonselective inducer of UGT enzymes, decreased CAN area under the curve (AUC) by 51%.11 When an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be used, the package insert suggests increasing the dose of CAN from 100 mg to 300 mg in patients with an eGFR 60 mL/min/1.73 m2.11 In patients with eGFR between 45 mL/min/1.73 m2 and 60 mL/min/1.73 m2 who require a UGT inhibitor, an alternative AHA should be considered. CAN AUC and Cmax increases of 20% and 36%, respectively, were observed in patients on concomitant digoxin and CAN 300 mg therapy digoxin alone.11 The package insert suggests that older adults taking CAN 300 mg with digoxin should be monitored for potential increased risk of

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adverse effects including hypoglycemia and hypotension.11 No reports were identified that clearly defined the risk of combination of loop diuretics and canagliflozin. However, given that both medications carry the risk of dehydration, additive risk cannot be ruled out. Cautious addition and slow titration of loop diuretics are prudent.11 Preemptive dose reduction of loop diuretics may be considered in patients that will have CAN added. Though CAN weakly inhibits cytochrome P450 enzymes 2B6, 2C8, 2C9, and 3A4, as well as P-glycoprotein, it is not expected to have a clinically significant effect on drugs metabolized by these enzymes.8

Cost The average wholesale unit price of CAN is $10.52 for both doses.12 CAN is a tier 3 medication on certain formularies and is tier 4 for Medicare Part D patients.13,14

Discussion/Conclusion Based on the evidence from literature, CAN is a new antihyperglycemic agent with a novel mechanism of action that is effective and safe for the treatment of T2DM in older adults. Results from the literature reviewed showed that treatment with CAN resulted in statistically significant and clinically important improvements in A1C compared with placebo in older adults with T2DM.4,7,9,10 Based on subgroup analyses, less reductions in A1C levels were observed in subjects younger than 65 years of age compared with subjects 65 years and older.4 Additional nonglycemic benefits with CAN were also discovered. Those randomized to CAN demonstrated reductions in both body weight and blood pressure (BP). Conflicting with these advantages may be the potential increase in LDL by CAN. However, the result of the CV meta-analysis did not indicate an increase in CV risk.9,10 Furthermore, the overall hazard ratio for CV events in the CANVAS trial also did not show an increased CV risk, but did raise concern that these early CV events (within the first 30 days of CAN use) may be related CAN-induced hemodynamic effects, reflected by changes in BP and renal function as well as the increased incidence of volume-depletion events. The increase in CV events was also not observed

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in other phase 3 trials where subjects did not have a high CV disease burden at baseline. CAN’s CV risk may be more prevalent in patients with high CV risk who are more sensitive to its hemodynamic effect. Considering this information is based on data from a 30-day period, clearly more long-term follow-up is needed. At this time, the potential CV risk of CAN does not outweigh the benefit. The rates of genital mycotic infections, osmotic diuresis, and volume-depletion related to CAN may limit its utility in the elderly and in long-term care facility residents. Older women with T2DM are at an increased risk for urinary incontinency, and polyuria, vaginal candidiasis, and UTIs all having the potential to cause or exacerbate this condition.15 The incidence of osmotic-diuresis and UTIs was higher with the 300 mg dose of CAN, and a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration) was observed. The largest increase associated with the use of loop diuretics, patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and patients 75 years of age and older.11 These data suggest that the 300 mg dose may not be appropriate for patients 75 years of age and older. Before starting CAN in elderly or long-term care facility residency, volume status of elderly patients should also be assessed. CAN should not be initiated in patients with evidence of dehydration (thirst, dry mouth, constipation, tenting skin, reduced urination/ sweating, weight loss, etc.). In long-term care facility residents on CAN, additional caution may be prudent; assessment of hydration status may be added to daily nursing rounds, and any change in mental status should prompt additional assessment of hydration status. Regarding drug interactions, CAN may need to be increased from the 100 mg dose to 300 mg in patients receiving UGT inducers (e.g., rifampin), have an eGFR ≥ 60 mL/min/1.73 m2, or require additional glycemic lowering. Patients receiving digoxin should have levels

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monitored appropriately while taking CAN 300 mg. In summary, CAN 100 mg and 300 mg has been shown to improve A1C levels, lower SBP, reduce body weight, and have an impact on HDL-C and triglyceride levels. Overall, CAN was well tolerated throughout the clinical trials in older patients with T2DM. AEs including genital mycotic infections, UTIs, volume-depletion-related AEs, and increased urination may limit this drug’s use in the elderly population. Other concerns such as the risk for CV events are still under investigation, and additional long-term studies are needed to assess this risk, some of which are ongoing.9,10 As more studies are performed in the elderly, deciding how CAN can be used in this population will be clearer. As of now, the risks and benefits of this medication should be evaluated for geriatric patients on an individual basis to decide if CAN is an appropriate choice.

Lindsey Elmore, PharmD, BCPS, is transitions of care clinical pharmacist, St. Vincent’s Hospital, Birmingham, Alabama. Sara Baggett is a 2014 PharmD candidate, McWhorter School of Pharmacy, Samford University. Jeffrey A. Kyle, PharmD, BCPS, is associate professor of pharmacy practice, McWhorter School of Pharmacy, Samford University, and clinical pharmacy specialist, Shelby Baptist Medical Center, Birmingham, Alabama. Jessica W. Skelley, PharmD, BCACP, is assistant professor of pharmacy practice, McWhorter School of Pharmacy, Samford University, and adjunct faculty, St.Vincent’s East Family Medicine residency program, Birmingham. For correspondence: Lindsey Elmore, PharmD, BCPS, St. Vincent’s Hospital Birmingham, 810 St. Vincent’s Drive, Birmingham, AL 35205, Phone: 205-939-7090; Fax: 205-930-2260; E-mail: Elmore. [email protected]. Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2014 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2014.335.

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Clinical Review References 1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2011. Available at http://www.cdc.gov/diabetes/pubs/factsheet11.htm. Accessed October 8, 2013. 2. American Diabetes Association. Standards of medical care in diabetes-2013. Diabetes Care. 2013;36 Suppl 1:S11-S66. 3. Kirkman MS. Diabetes in older adults: a consensus report. J Am Geriatr Soc 2012:1-15. Available at http://www.americangeriatrics.org/ search/?cx=008664580565903273424%3Auo2vk7ffzna&cof=FORID%3 A10&ie=UTF-8&q=eldery+adults+age+range&sa=%C2%A0. Accessed September 5, 2013. 4. Bode B, Stenlöf K, Sullivan D et al. Efficacy and safety of CAN treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract 2013;41:72-84. 5. U.S. FDA Approves Invokana (CAN) for the Treatment of Adults with Type 2 Diabetes. Johnson and Johnson Web site. Updated June 25, 2013. Available at http://www.jnj.com/news/all/us-fda-approves-invokanaCAN-for-the-treatment-of-adults-with-type-2-diabetes. Accessed June 24, 2013. 6. Kim Y, Babu A. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes. Diabetes Metab Syndr Obes 2012;5:313-27. 7. Yale J-F, Bakris G, Cariou B et al. Efficacy and safety of CAN in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013;15:463-73. 8. 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, placebocontrolled study. Diabetes Care 2013;36:2154-61. 9. Matthews D, Fulcher G, Perkovic V et al. Efficacy and safety of CAN, an inhibitor of sodium glucose co-transporter 2, added on to insulin therapy with or without oral agents in type 2 diabetes. Poster presented at The 48th Annual Meeting of the European Association for the Study of Diabetes (EASD); October 1-5, 2012; Berlin, Germany.

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10. Fulcher G, Matthews D, Perkovic V et al. CAN in subjects with type 2 diabetes mellitus inadequately controlled on sulfonylurea monotherapy: a CANVAS substudy. Poster presented at The 73rd Scientific Session of the American Diabetes Association (ADA); June 21-25, 2013; Chicago, IL. 11. INVOKANA™ [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. Available at http://www.invokanahcp.com/ prescribing-information.pdf. Accessed October 8, 2013. 12. Canagliflozin. In Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc.; updated August 1, 2013. Available at http://www.crlonline.com.ezproxy. samford.edu/lco/action/doc/retrieve/docid/patch_f/4230722. Accessed October 21, 2013. 13. Formulary decision highlights: June 12, 2013. GroupHealth Web site. Available at https://provider.ghc.org/open/providerCommunications/ highlights/june-2013.pdf. June 2013. Accessed August 9, 2013. 14. 2012-2013 3-tier formulary guide. BlueCrossBlueShield Association Web site. Available at https://www.excellusbcbs.com/wps/wcm/ connect/1786b4d6-ab4e-4844-8b9696b5a929952a/Excellus+3-tier+ formulary+WEB+7.1.13pdf?MOD=AJPERES&CACHEID=1786b4d6ab4e-4844-8b96 96b5a929952a. Accessed August 9, 2013. 15. Brown AF, Mangione CM, Saliba D et al. California Healthcare Foundation/American Geriatrics Society Panel on Improving Care for Elders with Diabetes. Guidelines for improving the care of the older person with diabetes mellitus. J Am Geriatr Soc 2003;51 Suppl Guidelines:S265-S280. 16. Cefalu WT, Leiter LA, Yoon KH et al. Efficacy and safety of CAN 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. The Lancet 2013;382:941-50. 17. Inagaki N, Kondo K, Yoshinari T et al. Efficacy and safety of CAN in Japanese patients with type 2 diabetes: a randomized, double-blind, placebocontrolled, 12-week study. Diabetes Obes Metab 2013;15:1136-45. 18. Chau E. A Paradigm Shift in Diabetes Therapy—Dapagliflozin and Other SLGT-2 Inhibitors. Discov Med 2011;11:255-63. Available at http:// www.discoverymedicine.com/Edward-C-Chao/2011/03/23/a-paradigmshift-in-diabetes-therapy-dapagliflozin-and-other-sglt2-inhibitors/. Accessed November 4, 2013.

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VOL. 29, NO. 5

A review of the efficacy and safety of canagliflozin in elderly patients with type 2 diabetes.

To review the efficacy and safety of canagliflozin (CAN) in elderly patients with type 2 diabetes mellitus (T2DM)...
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