Canagliflozin: a Novel Agent for the Treatment of Type 2 Diabetes Mellitus Correspondence Course Program Number: 0171-9999-13-072-H01-P 1

CE Canagliﬂozin: A Novel Agent for the Treatment of Type 2 Diabetes Mellitus

By Marquita D. Bradshaw, Pharm.D., BCACP and Rikki L. Tonet, Pharm.D. Candidate 2014

Objectives INTRODUCTION • Describe the pathophysiological defects in Type 2 T2DM is one of the four clinical classes of diabetes Diabetes Mellitus (T2DM) incorporated in the omi- identified which results from a progressive insulin nous octet secretory defect on the background of insulin re- • Describe the mechanism of action of canagliflozin sistance.2 Signs and symptoms of T2DM include • Identify the potential place in therapy of cana- polyuria, polydipsia, and polyphagia which may not gliflozin be overt. Often patients with T2DM are not diag- • Summarize patient counseling points when dispens- nosed until complications appear; therefore resulting ing canagliflozin in subsequent reduction in quality of life if diabetes • Identify available strengths of canagliflozin (Phar- remains uncontrolled. macy technicians***) Approximately 25.8 million children and adults in Conflict of interest statement: There is no conflict the United States are living with diabetes, including 7 of interest involved in writing this article or in the million who are currently undiagnosed.3 This equates subject matter of this article. to 8.3% of the population in the United States. In 2010, South Carolina had the fifth highest prevalence Abstract: Several oral and injectable agents are of diabetes in the nation.4 The prevalence of diabetes available for the treatment of Type 2 Diabetes Melli- in South Carolina is presently 9.6% and has increased tus (T2DM). A recent consensus statement published more rapidly than the national rate.4 by the American Diabetes Association emphasizes a patient-centered approach.1 Canagliflozin belongs Previously it was thought that a triumvirate was to a novel therapeutic class. It is the first agent in its responsible for the pathophysiological defects occur- therapeutic class approved by the Food and Drug ring in T2DM including muscle, liver, and beta cell Administration (FDA) for use adjunct to diet and involvement. Recently, five additional pathophysio- exercise to improve glycemic control in adults with logical defects have been described including fat cell T2DM. Canagliflozin affords the opportunity for (accelerated lipolysis), gastrointestinal tract (incretin patients previously managed with diet, exercise, and deficiency/resistance), alpha cell (hyperglucagone- other oral agents to achieve even further hemoglobin mia), kidney (increased glucose reabsorption) and the A1c (HbA1c) lowering. Canagliflozin is adminis- brain (insulin resistance).5 It is proposed that multiple tered orally and may be a viable option for patients pathophysiological defects warrant treatment with who refuse insulin and have not achieved optimal combination therapy targeting several defects (Table glycemic control. However, it is not devoid of unfa- 1). vorable adverse effects. The objective of this article is to briefly discuss the pathophysiological defects of Since 1995, when only two medication classes were T2DM and potential role of therapy for canagliflozin available for the treatment of T2DM, many have in the treatment of T2DM. been approved by the FDA. Among these medication classes are dipetidyl peptidase IV inhibitors, Key words: canagliflozin, diabetes mellitus, sodium glucagon- like-peptide (GLP)-1 agonists, and the new glucose co-transporter 2 receptor inhibitor sodium glucose co-transporter receptor inhibitors (SGLT). Canagliflozin (Invokana™, Janssen Pharma- ceuticals) is the first agent included in the therapeutic

36 Palmetto Pharmacist • Volume 53 Number 3 CE

Table 1. Ominous Octet and Medications to Target Defects class of sodium glucose co-transporter Origin of Defect Pathophysiologic Defect Medication Class receptor inhibitors, approved March 2013, Targeting Defect for use in the United States. It is indicated Muscle Insulin resistance TZDs (pioglitazone, rosiglitazone) for use as an adjunct to diet and exercise Liver Insulin resistance Biguanides (metformin) to improve glycemic control in adults with and TZDs β-cell Insulin resistance ------T2DM.6 Fat cell Accelerated lipolysis TZDs Gastrointestinal tract Incretin deficiency/resistance GLP-1 (exenatide, liraglutide), DPP-IV MECHANISM OF ACTION inhibitors (sitagliptin, saxalipitin, linagliptin, Homeostasis in the body is maintained via alogliptin) and amylin multiple organ systems. One of the major α-cell Hyperglucagonemia ------Kidney Increased glucose reabsorption Sodium glucose contributors to homeostasis of multiple transporter receptor inhibitor (canagliflozin) endogenous and exogenous substances is Brain Insulin resistance Dopamine-2 Agonist the kidneys. The kidneys are well known (bromocriptine) TZDs = Thiazolidinediones; DPP = dipetidyl peptidase; GLP =glucagon like peptide for the maintenance of blood pressure; however they play a substantial role in the with glimepiride vs. placebo (-0.85,-1.06, homeostasis of blood glucose as well. The primary -0.13%, respectively), with metformin and a sulfo- mechanisms in which the kidneys regulate blood nylurea vs. sitagliptin (-1.03, 0.66%, respectively), glucose are through the release of glucose into blood with metformin and a thiazolidinedione (-0.89, -1.03, via gluconeogenesis and glucose reabsorption in the -0.26, respectively), and in combination with insulin proximal convoluted tubule (PCT).7 (-0.63,-0.72, 0.01%, respectively). Associated mean reductions in HbA1c (absolute reductions of 0.45– Glucose reabsorption is accomplished with the ac- 0.92%), fasting plasma glucose (decreases ranged tive transport of glucose by sodium-coupled glucose from 16.2% to 42.4%) and weight loss ranging from co-transporters (SGLT1 and SGLT2) found in the 0.7 to 3.5 kg were also observed in clinical trials.12-21 kidneys.8 SGLT1 is located in the heart, intestine, trachea, and kidney, whereas SGLT2 is located only Dapagliflozin, an agent in the same therapeutic class, in the kidney.9 SGLT1 is shown to reabsorb 10% of has been approved for use in Europe since 2012. filtered glucose reabsorption in the S3 segment of The body of literature supporting its efficacy is also the PCT, where the SGLT2 has been identified to available. Decreased risk in macrovascular compli- conduct 90% of reabsorption in the S1 segment of cations has not been established. In July 2011, an the PCT.10 The mechanism in which this new class of FDA Advisory Committee voted against the approval drugs (SLGT2 inhibitors) works is through inhibition of dapagliflozin as they cited higher rates of breast of these SGLT2 co-transporters ultimately resulting and bladder cancer in the treatment arms of trials in decreased renal reabsorption of the filtered glu- analyzed. 22 Further clinical trials with an extended cose.6 This inhibition of glucose reabsorption results duration are necessary. in increased renal glucose excretion into the urine defined as glucosuria. This increased excretion of PHARMACOKINETICS glucose may have beneficial effects of weight loss.11 In regards to absorption, canagliflozin is found to reach peak plasma concentrations within 1-2 hours THERAPEUTIC EFFICACY postdose.6 The 100 mg oral tablet has an apparent Since the discovery of canagliflozin in the late half-life of 10.6 hours as compared to the 300 mg 2000s, its safety and effectiveness was evaluated in tablet which possesses a 13.1 hour half-life. Steady- nine clinical trials involving over 10,000 patients state plasma concentration was reached after 4-5 days with T2DM, including patients with chronic kidney of administration.6 disease.12-21 As monotherapy at week 26, a statisti- cally significant reduction in HbA1c was achieved Canagliflozin can be administered without regards from baseline with canagliflozin 100 and 300 mg to meals, but improved glycemic control may occur compared with placebo (−0.77,−1.03 and 0.14%, when dosed before the first meal of the day due to respectively).6 Canagliflozin has also been studied in delayed gastrointestinal absorption of glucose. The combination with metformin showing a reduction in oral bioavailability of canagliflozin is nearly 65%.6 HbA1c from baseline with 100 mg and 300 mg dose versus placebo (-0.79, -0.94, -0.17%, respectively), Canagliflozin is 99% plasma protein bound, mainly

Palmetto Pharmacist • Volume 53, Number 3 37 CE to albumin. The mean apparent volume of distribu- once daily, has an eGFR greater than 60 mL/min/1.73 tion was 119 L after single intravenous (IV) adminis- m2, and requires additional glycemic control.6 Other tration. Metabolism is mainly through O-glucuroni- antidiabetic agents should be considered for use in dation by UGT1A9 and UGT2B4, producing two patients who require additional glycemic control and inactive metabolites. In humans, small amounts (7%) do not meet this criteria. are metabolized through CYP3A4.6 Conversely, an increase in the area AUC and mean The average clearance of canagliflozin was 192 peak drug concentration (Cmax) of digoxin (20% ml/min when administered by IV route to healthy and 36%, respectively) is expected when co-admin- individuals. Approximately 33% and 41.5% of the istered with canagliflozin 300 mg. Patients taking administered dose was excreted in the urine and fe- canagliflozin with concomitant digoxin should be ces, respectively. The renal clearance of canagliflozin monitored appropriately.6 ranged from 1.30 to 1.55 mL/min.6 SIDE EFFECTS DOSING Four placebo-controlled pooled studies revealed the Canagliflozin is available as 100 mg and 300 mg five most common adverse effects as female genital tablets. The initial recommended dose for cana- mycotic infections, urinary tract infections, increased gliflozin is 100mg by mouth prior to the first meal of urination, male genital mycotic infections and vul- the day. Maximum adult daily doses of 300 mg may vovaginal pruritus. Evidence supports that patients be warranted in patients needing additional glycemic with a history of genital mycotic infections and uncir- control with normal renal function, defined as an cumcised males were more likely to develop genital estimated glomerular filtration rate (eGFR) greater mycotic than or equal to 60mL/min/1.73m2. Canagliflozin is associated with increases in serum creatinine (SCr) infections. This subset of patients should be moni- and decreased eGFR. It is important to note the need tored and treat appropriately. Lab parameters and for baseline renal function tests before initiation of associated symptomology should be monitored to co- therapy as well as regular renal function monitoring incide with precautions including hyperkalemia, hy- throughout the course of treatment in these patients.6 poglycemia, increase in low density lipoprotein, and impairment in renal function.6 Hypoglycemia was Patients with moderate renal impairment, eGFR more likely to occur in patients taking canagliflozin 45-60 mL/min/1.73m2, are recommended to main- and insulin or a secretagogue. Hyperkalemia was tain maximum daily doses of 100mg, and careful more likely to occur in patients taking other medica- monitoring of SCr and eGFR. Patients with severe tions also known to increase potassium including renal impairment, eGFR less than 45 mL/min/1.73m2 angiotensin receptor blockers (ARB), angiotensin should avoid the use of canagliflozin. Hypovole- converting enzyme inhibitors (ACEI), or aldosterone mic patients should avoid use of canagliflozin, until antagonists. euvolemia is restored, due to the increased risk of symptomatic hypotension. No dosage adjustments are The FDA is necessitating five postmarketing studies needed in patients with hepatic impairment.6 be conducted by the manufacturer, three of which target the adult population: a cardiovascular outcomes DRUG INTERACTIONS trial; an enhanced pharmacovigilance program to Co-administration of canagliflozin with UDP-gluc- monitor for malignancies, serious cases of pancreati- uronosyltransferase (UGT) inducers poses a drug tis, severe hypersensitivity reactions, photosensitivity interaction and a dose increase may be warranted. reactions, liver abnormalities, and adverse pregnancy Canagliflozin administered with nonselective induc- outcomes; and a bone safety study.23 ers of UGT enzymes, such as rifampin, decrease canagliflozin efficacy by a 51% reduction in the area SPECIAL POPULATIONS under the curve (AUC).6 Clinicians choosing to initi- Pediatrics and Geriatrics ate concomitant administration of UGT inducers with The prevalence of T2DM in children is increas- canagliflozin should consider increasing the dose to ing. Use of canagliflozin has not been established 300 mg once daily under the following conditions: in patients under the age of 18, due to insufficient patient is currently tolerating canagliflozin100 mg evidence of safety and efficacy. Of the five aforemen-

38 Palmetto Pharmacist • Volume 53 Number 3 Table 2. Patient Counseling Take Home Points CE Side effects x This medication may affect how your immune system works and may cause a yeast infection or urinary tract infection. leading to the conclusion that cana- x A change in electrolytes has occurred in patients taking gliflozin use should be avoided in canagliflozin. nursing mothers.6 Drug Interactions x Some medications interact with canagliflozin. x Inform your doctor, pharmacist, or other healthcare professionals CONCLUSIONS if you have started a new medication or stopped any medications Canagliflozin represents the first since your last visit including rifampin or digoxin. of many agents in its class. It holds x Dose adjustments may be made if you are taking medications that interact with canagliflozin. promise to a unique mechanism to treat T2DM. The place of therapy Administration x For optimal results, canagliflozin should be taken with the first for canagliflozin has yet to be elu- meal of each day. cidated. Expected HbA1c lowering Laboratory Test x Canagliflozin will cause you to test positive for glucose in your observed was comparable to other urine. oral agents currently marketed to treat T2DM including alpha gluco- tioned postmarketing studies to be conducted by the sidase inhibitors, meglitinides, and manufacturer, two are pediatric studies including a dipeptidyl peptidase inhibitors. Conversely, distin- pharmacokinetic and pharmacodynamic study and a guishing adverse effects may limit its use. Perhaps it safety and efficacy study.23 Recently published rec- is a viable option for adults with T2DM who can- ommendations regarding the management of T2DM not achieve glycemic control with multiple agents favor the use of metformin as ﬁrst-line therapy for but refuse injectable medications. Extensive patient children and adolescents at the time of diagnosis.24 counseling is warranted due to drug interactions, administration, and side effects (Table 2). A study found that canagliflozin use in geriatric patients was associated with increased risk of hypo- RESOURCES FOR HEALTH CARE PROFES- volemic related adverse events such as hypotension, SIONALS IN SOUTH CAROLINA syncope, dehydration, and dizziness. These effects Useful Websites were reported at higher levels in geriatric patients • Endocrinology-Diabetes Initiative of South Caro- taking daily doses of 300 mg or patients 75 years of lina: http://clinicaldepartments.musc.edu/medi- age or older.6 cine/divisions/endocrinology/dsc • South Carolina Department of Health and En- Pregnancy and Lactation vironmental Control Diabetes Prevention and Canagliflozin is categorized as pregnancy level C. Control: http://www.scdhec.gov/health/chcdp/ There is no human data available for teratogenic diabetes/links.htm effects from use during pregnancy and lactation. In • American Diabetes Association: http://www. studies using rats, it was observed that canagliflozin diabetes.org/ may affect renal development and maturation. It was • National Institute of Diabetes and Digestive and reported that doses of 300 mg resulted in a greater Kidney Diseases (NIDDK), National Institutes than or equal to 0.5 fold increased kidney weights of Health (NIH): http://www2.niddk.nih.gov/ or and renal pelvic and tubular dilation. This expo- http://www.nih.gov/ sure in rats was comparable to the second and third • National Diabetes Education Program (NDEP): trimester of pregnancy in humans, concluding that http://ndep.nih.gov/ canagliflozin use during pregnancy may result in • Juvenile Diabetes Research Foundation Interna- fetal malformations. Careful consideration must be tional (JDRF): http://jdrf.org/ made if initiation during pregnancy is desired, and • International Diabetes Federation (IDF): http:// should only be used if the potential benefit outweighs www.idf.org/ potential risk to fetus.6 • American Association of Clinical Endocrinolo- gists: https://www.aace.com/ Evidence is lacking on use during lactation in hu- • The Endocrine Society: http://www.endo-soci- mans, though a study in rats found that canagliflozin ety.org/ is secreted in milk of rats at levels up to 1.4 times • American Association of Diabetes Educators: that of maternal plasma levels. These levels in rats http://www.diabeteseducator.org/ have shown malformation of the developing kidney,

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REFERENCES canagliflozin, a sodium glucose co transporter inhibitor 1. Inzucchi SE, Bergenstal RM, Buse JB et al. (abstract 43-LB). Diabetes. 2011; 60 (suppl 1A):LB12. Management of Hyperglycemia in Type 2 Diabetes: A 16. Nyirjesy P, Zhao Y, Usiskin K et al. Efficacy of Patient-Centered Approach: position statement of the canagliflozin (CANA), a sodium glucose co-transporter American Diabetes Association (ADA) and the Euro- 2 inhibitor, on vulvovaginal Candida colonization and pean Association for the Study of Diabetes (EASD). symptomatic vulvovaginal candidiasis in patients with Diabetes Care. 2012; 35 (6): 1364-79. type 2 diabetes mellitus. Curr Med Res Opin. 2012; 28 2. American Diabetes Association. Standards of (7) :1173-8. medical care in diabetes-2013.Diabetes Care. 2013;36 17. Inagaki N, Kondo K, Iwaski T et al. Cana- (suppl 1):s11-66. gliflozin, a novel inhibitor of sodium glucose co-trans- 3. Diabetes Statistics [Internet]. American Dia- porter 2 (SGLT2) improves glycemic control and re- betes Association. http://www.diabetes.org/diabetes-ba- duces body weight in Japanese type 2 diabetes mellitus sics/diabetes-statistics/. Accessed April 15 2013. (T2DM) (abstract 999-P). Diabetes 2011: 60. 4. Heidari, K and Myers P. Brief Update on the 18. Wexler D, Vandebosch A, Usiskin K et al. Burden of Diabetes in South Carolina. Am J of Med Study of electrocardiogram intervals in healthy adults Sci. 2013; 345(4):302-306. receiving single oral doses of canagliflozin (abstract 5. DeFronzo RA. From the Triumvirate to the 2177-PO). Diabetes. 2010; 59 (suppl 1): A571. Ominous Octet: A New Paradigm for the Treatment of 19. Sarich T, Devineni D, Ghosh A et al. Cana- Type 2 Diabetes Mellitus. Diabetes. 2009; 58:773-795. gliflozin, a novel inhibitor of sodium glucose co-trans- 6. Invokana™ [package insert]. Titusville, NJ: porter 2, increases 24-h urinary glucose excretion and Janssen Pharmaceuticals Incorporated; 2013. decreases body weight in obese subjects (abstract 567- 7. Wright EM, Hirayama BA, Loo DF. Active P). Diabetes 2010; 59 (suppl 1): A155. sugar transport in health and disease. J Int Med. 2007; 20. Sha S, Devineni D, Ghosh A et al. Cana- 261(1):32-43. gliflozin, a novel inhibitor of sodium glucose co-trans- 8. Triplitt CL. Understanding the kidneys’ role in porter 2, dose dependently reduces calculated renal blood glucose regulation. Am J Manag Care. 2012;18(1 threshold for glucose excretion and increases urinary Suppl):S11-6. glucose excretion in healthy subjects. Diabetes Obes 9. Nishimura, M. Naito S. Tissue-Specific mRNA Metab 2011; 13 (7): 669-72. Expression Profiles of Human ATP-Binding Cassette 21. Yale JF, Bakris G, Cariouu B, Yue D, David- and Solute Carrier Transporter Superfamilies. Drug Neto E, Xi L, et al. Efficacy and safety of canagliflozin Metab Pharmacokinet. 2005; 20:452-477. in subjects with type 2 diabetes and chronic kidney 10. Marsenic O. Glucose control by the kidney: disease. Diabetes Obesity Metab 2013; 15:463-473. an emerging target in diabetes. Am J Kidney Disease. 22. Burki TK. FDA rejects novel diabetes drug 2009;53(5):875-883 over safety fears. Lancet 2012; 279 (9815):507. 11. Neumiller JJ, White JR, Campbell RK. 23. Copeland KC, Silverstein J, Moore KR, Prazar Sodium-glucose co-transport inhibitors. Drugs. GE, Raymer T, Shiffman RN, et al. Management of 2010;70:377-385. Newly Diagnosed Type 2 Diabetes Mellitus (T2DM) in 12. Devineni D, Morrow L, Hompesh M et al. Children and Adolescents. Pediatrics 2013; 131:364– Canagliflozin improves glycaemic control in subjects 382. with Type 2 diabetes not optimally controlled on insu- 24. Food and Drug Administration [Internet]. FDA lin. Diabetes Obes Metab. 2012; 14:539-45. approves Invokana to treat type 2 diabetes http://www. 13. Rosenstock J, Arbit D, Usiskin K et al. Cana- fda.gov/NewsEvents/Newsroom/PressAnnouncements/ gliflozin, an inhibitor of sodium glucose co-transporter ucm345848.htm. Accessed April 15 2013. 2, improves glycemic control and lowers body weight in subjects with type 2 diabetes on metformin (abstract 77-OR). Diabetes. 2010; 59 (suppl 1): A21. 14. Sha S, Devineni D, Gosh et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, improved glucose control in subjects with Type 2 diabetes and was well tolerated (abstract 568-P). Diabetes. 2010; 59 (suppl 1): A155. 15. Nicolle L, Usiskin K, Capuano G et al. No increase in bacteriuria or urinary tract infections in patients with type 2 diabetes mellitus treated with

40 Palmetto Pharmacist • Volume 53 Number 3 Canagliflozin: A Novel Agent for the Treatment of Type 2 Diabetes Mellitus Correspondence Course Program Number: 0171-9999-13-072-H01-P 1. Complete and mail entire page. SCPhA members can take the Journal CE for free; $15 for non-members. Check must accompany test. You may also complete the test and submit payment online at www.scrx.org. 2. Mail to: Palmetto Pharmacist CE, 1350 Browning Road, Columbia, SC 29210-6309. 3. Continuing Education statements of credit will be issued within 6 weeks from the date the quiz, evaluation form and payment are received. 4. Participants scoring 70% or greater and completing the program evaluation form will be issued CE credit. Participants receiving a failing grade on any examination will have the examination returned. The participant will be permitted to retake the examination one time at no extra charge.

South Carolina Pharmacy Association is accredited by the Accreditation Council for Pharmacy Education as providers for continuing pharmacy education. This article is approved for 1 contact hour of continuing pharmacy education credit (ACPE UPN 0171-9999-13-072-H01-P ). This CE credit expires 6/28/2016. Name: ______License #: ______Address: ______City: ______State: _____ Zip: ______Phone: ______Email:______NABP eID: ______Birth Month/Birth Date (MMDD): ______Evaluation: Circle the appropriate response Did the article achieve the stated objectives? Not at all 1 2 3 4 5 Completely Overall evaluation of the article? Poor 1 2 3 4 5 Excellent Was the information relevant to your practice? No 1 2 3 4 5 Yes How long did it take you to read the article and complete the exam? ______CE credit will ONLY be awarded when a submitted test is accompanied by completing the evaluation above or online at www.scrsx.org

Learning Assessment Questions: 5. Canagliflozin has been studied in combination with all the following EXCEPT: 1. The pathophysiologic defect in Type 2 Diabetes Mel- litus at the level of the kidney is: A. Insulin B. Insulin + Sitagliptin A. Hyperglucagonemia C. Metformin + Pioglitazone B. Increased glucose reabsorption D. Metformin +Glimepiride C. Incretin deficiency D. Insulin resistance 6. Which of the following is NOT a common side effect experienced in patients on canagliflozin therapy? 2. Canagliflozin works to inhibit: A. Changes in urination A. Glucagon-like-peptide 1 B. Upper respiratory tract infection B. Insulin growth factor 1 C. Urinary tract infection C. Sodium glucose co-transporter 2 D. Yeast infection of the penis

7. Inhibition of sodium glucose transport 2 results in a: 3. Canagliflozin is indicated for use in adult patients with: A. Higher renal threshold for glucose B. Decrease in sodium reabsorption A. Diabetic Ketoacidosis C. Decrease in urinary glucose excretion B. Hyperglycemic Hyperosmolar State D. Reduction of reabsorption of filtered glucose C. Type 2 Diabetes Mellitus D. Type 1 Diabetes Mellitus 8. When administered concomitantly with an angiotensin receptor blocker (ARB), angiotensin converting enzyme 4. Canagliflozin is supplied as a tablet in which of the inhibitor (ACEI), or aldosterone antagonist, canagliflozin may following doses? cause:

A. 50 and 100 mg A. Hyperkalemia B. 100 and 300 mg B. Hypernatremia C. 200 and 300 mg C. Hypomagnesemia D. 200 and 400 mg D. Hyponatremia

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