WHAT’S NEW IN DIABETES

Canagliflozin: A new option for managing diabetes Molly Livingston, PharmD; Jennifer N. Clements, PharmD, BCPS, CDE, BCACP

ABSTRACT Canagliflozin is a sodium glucose cotransporter 2 inhibitor for patients with type 2 diabetes and can be given as monotherapy or in combination with other agents, including insulin. Taken orally once daily, canagliflozin can reduce weight and BP, but has been associated with genital mycotic infections. Keywords: sodium glucose cotransporter 2, canagliflozin, glycosuria, type 2 diabetes, hyperglycemia, genital mycotic infections

T

ype 2 diabetes is a chronic, progressive disease involving multiple organ defects, which cause hyperglycemia. According to the American Diabetes Association (ADA), type 2 diabetes is a metabolic problem of glucose use in the body, mainly driven by insulin resistance and progressive defects in insulin secretion.1 Table 1 summarizes the definition and pathophysiology of type 2 diabetes.1,2 Chronic hyperglycemia can lead to microvascular complications such as retinopathy, neuropathy, and nephropathy, and macrovascular events including myocardial infarction and stroke.3 In 2012, the ADA and European Association for the Study of Diabetes published guidelines for the management of type 2 diabetes.4 These guidelines recommend metformin as first-line therapy unless a patient has a contraindication to the drug. Second-line agents can be initiated if glycemic control is not achieved after 3 months of metformin. Second-line agents include sulfonylureas, thiazolidinediones, dipeptidyl-peptidase 4 inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and basal insulin. The choice of a second-line agent should be based on efficacy, adverse reaction profile, cost, injection preference, At the time this article was written, Molly Livingston was a student in the doctor of pharmacy program at Presbyterian College School of Pharmacy in Clinton, S.C. Jennifer N. Clements is an associate professor in the Department of Pharmacy Practice at Presbyterian College School of Pharmacy. The authors have disclosed no potential conflicts of interest, financial or otherwise. Mark E. Archambault, DHSc, PA-C, department editor DOI: 10.1097/01.JAA.0000453247.76333.09 Copyright © 2014 American Academy of Physician Assistants

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Key points Canagliflozin can be used as add-on therapy, or as monotherapy if other options are contraindicated or have been ineffective or intolerant. Canagliflozin is well tolerated and has been shown to improve A1C levels, body weight, and BP. Before initiating canagliflozin, counsel patients about the drug’s glycemic effects, possible adverse reactions, and dosing instructions. More trials are needed to determine canagliflozin’s longterm and cardiovascular safety.

and the patient’s current glycemic issue (for example, fasting or postprandial). The American Association of Clinical Endocrinologists’ guidelines for type 2 diabetes and obesity management also recommend metformin as first-line therapy unless the patient has a contraindication.5 After 3 months of monotherapy, if the patient has not achieved adequate glycemic control, second-line agents can be initiated and are recommended in the following order based on the evidence: GLP-1 agonists, dipeptidyl-peptidase 4 inhibitors, thiazolidinediones, sodium-glucose cotransporter 2 (SGLT2) inhibitors, basal insulin, colesevelam, bromocriptine, alpha-glucosidase inhibitors, and meglitinides/ sulfonylureas. The specific agent is determined by the patient’s degree of hyperglycemia, risk of hypoglycemia, and the drug’s effect on patient weight. All oral and/or injectable medications should be combined with lifestyle modifications.4,5 SGLT-2 INHIBITION: A NOVEL MECHANISM OF ACTION In 2013, the FDA approved canagliflozin, the first SGLT2 inhibitor available as an adjunct to diet and exercise. The drug is indicated to improve glycemic control in adults with type 2 diabetes. The kidneys regulate glucose via gluconeogenesis and reabsorption of glucose within the glomerular filtrate. For patients with normal glucose regulation, about 180 grams of glucose can be filtered by the glomerulus. All filtered glucose can be reabsorbed and returned to the circulation. Sodium-glucose cotransporter 1 www.JAAPA.com

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WHAT’S NEW IN DIABETES TABLE 1.

Definition and pathophysiology of type 2 diabetes1,2

Definitions Glycemic test

Diagnostic criteria

Fasting blood glucose: Measures the ability of endogenous or exogenous insulin to prevent hyperglycemia by regulating glucose anabolism and catabolism

≥ 126 mg/dL on two separate occasions

Random glucose: Assesses glycemic control throughout the day regardless of meals

Symptoms of diabetes (including polyuria, polydipsia, polyphagia, and unexplained weight loss) with random glucose ≥ 200 mg/dL

2-hour oral glucose tolerance test (OGTT): Measures both the ability of the pancreas to secrete insulin following a glucose load and the body’s response to insulin

75 grams OGTT with a 2-hour glucose ≥ 200 mg/dL

A1C: Reflects mean glucose control over 3 months and incorporates fasting and postprandial glucose levels

≥ 6.5%

Pathophysiology Organ

Defect

Pancreas

• Beta-cell dysfunction • Inadequate insulin secretion

Peripheral muscle

• Reduced glucose use • Insufficient glycogen storage

Liver

• Increased glucagon production during fed state • Increased glucose production during fasting state

Adipose tissue

• Increased rate of lipolysis in the fed state • Increased free fatty acid release from adipocytes

Brain

• Increased appetite • Abnormal regulation of metabolism

Gastrointestinal

• Rapid gastric emptying • Gastroparesis

Kidney

• Reabsorption of glucose after filtration • Increased urinary albumin excretion • Possible development of proteinuria

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(SGLT1) is located mainly in the intestines and the late proximal tubules of the kidneys. SGLT1 is responsible for only 10% of glucose reabsorption in the kidneys; SGLT2 is the main transporter, involved in reabsorbing 90% of filtered glucose from the proximal tubules. In patients with type 2 diabetes, overexpression of SGLT2 receptor increases glucose reabsorption and causes chronic hyperglycemia. Canagliflozin prevents the reabsorption of filtered glucose by selectively inhibiting SGLT2 and thereby, inducing glycosuria and decreasing plasma glucose levels.6,7 This novel mechanism for glycemic control (excreting glucose through the urine) does not rely on endogenous insulin production, nor does it stimulate insulin secretion. EFFICACY OF CANAGLIFLOZIN Canagliflozin has been studied extensively as monotherapy and combination therapy, including in patients with renal impairment, older adults, and patients with a history of cardiovascular complications.8-10 Upon FDA approval, five postmarketing safety studies were started.11 These five studies focus on cardiovascular outcomes, pharmacovigilance, bone safety, and use in children (two studies). Canagliflozin has not been studied headto-head with other SGLT2 inhibitors such as dapagliflozin. As monotherapy, canagliflozin 100 mg and 300 mg once daily lowered hemoglobin A1C by 0.77% and 1.03% and reduced weight by 1.9 kg and 2.9 kg, respectively.12 This article focuses on the evidence of canagliflozin as an add-on agent. Table 2 outlines the inclusion criteria and interventions. In comparison to sitagliptin, canagliflozin has been studied as combination therapy with metformin. The change in A1C was evaluated from baseline to 12 weeks. Other outcomes included change in metabolic parameters, including fasting blood glucose, BP, and Volume 27 • Number 9 • September 2014

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Canagliflozin: A new option for managing diabetes

TABLE 2.

Inclusion criteria of canagliflozin as an add-on agent

Reference

Inclusion criteria

Intervention

Rosenstock and colleagues13

Subjects had type 2 diabetes and were receiving more than 1,500 mg per day of metformin for longer than 3 months.

After a screening phase, patients were randomized to canagliflozin 50 mg once daily, 100 mg once daily, 200 mg once daily, 300 mg once daily, 300 mg twice daily, sitagliptin 100 mg per day, or placebo.

Schernthaner and colleagues14

• Subjects were men and women age 18 years or older with type 2 diabetes who were using the combination of metformin and sulfonylurea therapy at maximally or near-maximally effective doses. • Subjects entered had an A1C of 7% to 10.5%.

Patients were randomized to 300 mg of canagliflozin or 100 mg of sitagliptin daily.

Cefalu and colleagues15

• Subjects had inadequately controlled with metformin over a 52-week treatment period. • Subjects were ages 18 to 80 years, had type 2 diabetes and A1Cs of 7% to 9.5%, and were receiving metformin therapy for 10 weeks.

• After the placebo run-in period, participants were randomly assigned canagliflozin 100 mg or 300 mg once daily or glimepiride. • Titration of glimepiride ranged from a starting dose of 1 mg to a maximum dose of 6 mg or 8 mg. • Glycemic rescue therapy with pioglitazone was available for patients. More patients were given pioglitazone in the glimepiride group (11%) than in the canagliflozin 100 mg (7%) and 300 mg (5%) groups.

weight. Baseline A1C (7.6% to 8%) was reduced by 0.76% and 0.92% with 100 mg and 300 mg once-daily doses, respectively. Sitagliptin 100 mg per day provided a 0.74% reduction in the primary outcome; however, canagliflozin improved metabolic measurements, such as weight (2.6 kg and 3.4 kg reduction with 100 mg and 300 mg doses) and fasting blood glucose (25.2 mg/dL with both canagliflozin doses).13 Another study compared canagliflozin 300 mg and sitagliptin 100 mg once daily to determine if canagliflozin causes a further reduction in A1C from baseline than sitagliptin in a 52-week treatment period. After a 2-week placebo run-in period, subjects were randomly assigned to receive either agent. Canagliflozin 300 mg once daily demonstrated a 56% greater reduction in A1C than sitagliptin 100 mg once daily at 52 weeks (1.03% versus 0.66%). A greater proportion of subjects treated with canagliflozin (47.6%) compared with sitagliptin (35.3%) achieved A1Cs less than 7%. Significantly greater reductions in fasting plasma glucose from baseline were observed with canagliflozin (-29.9 mg/dL) compared with sitagliptin (-5.9 mg/dL). Body weight decreased by 2.5% with canagliflozin and increased by 0.3% with sitagliptin.14 The efficacy of canagliflozin was compared with glimepiride as add-on therapy in patients with type 2 diabetes. For the primary endpoint, the A1C from baseline to week 52 was reduced with each treatment. Canagliflozin 100 mg was inferior to glimepiride, but canagliflozin 300 mg was superior to glimepiride. Canagliflozin 100 mg and 300 mg reduced body weight; glimepiride slightly increased body weight. The proportion of patients achievJAAPA Journal of the American Academy of Physician Assistants

ing A1C less than 7% was similar with glimepiride (56%), canagliflozin 100 mg (54%), and canagliflozin 300 mg (60%).15 SAFETY OF CANAGLIFLOZIN Short-term safety issues such as urinary tract infections and genital infections have been reported with canagliflozin because high glucose levels in the urine promote an environment for bacterial and fungal growth. No long-term evidence (more than 2 years) exists for this agent. Table 3 summarizes the safety outcomes of canagliflozin from clinical trials. Canagliflozin is contraindicated in patients with a history of serious hypersensitivity reaction to the medication and patients with severe renal impairment (estimated glomerular filtration rate [GFR] less than 30 mL/min/1.73m 2), end-stage renal disease, or on dialysis. Canagliflozin is not recommended in patients with severe hepatic impairment. The discontinuation rate was higher with sitagliptin (44.4%) than with canagliflozin (32.6%).14 A total of 96 patients discontinued glimepiride, 88 discontinued canagliflozin 100 mg, and 105 discontinued canagliflozin 300 mg.15 No patients discontinued the study because of an adverse reaction when studied over 28 days.12 DOSING AND ADMINISTRATION Canagliflozin is available in 100 mg and 300 mg tablets. The starting dose is 100 mg once daily. The dose should be administered before the first meal of the day. If additional glycemic control is required, the dose can be www.JAAPA.com

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WHAT’S NEW IN DIABETES

Summary of safety outcomes with canagliflozin12-15 TABLE 3.

Hypoglycemia • Compared with placebo, canagliflozin was associated with a low risk of hypoglycemia (less than 5%) as monotherapy or in combination with metformin. • The risk increases to 50% with insulin and 40% with sulfonylurea, compared with 30% and 40%, respectively, in the placebo arm. • The proportion of subjects having at least one hypoglycemic episode was similar with canagliflozin (43.2%) and sitagliptin (40.7%). Incidence of severe hypoglycemic episodes was also similar with canagliflozin (4%) and sitagliptin (3.4%). • The proportion of patients with documented hypoglycemic episodes was significantly lower with canagliflozin 100 mg (6%) and 300 mg (5%) than with glimepiride (34%). • A lower dose of insulin or sulfonylurea may be required to minimize the risk of hypoglycemia when used in combination with canagliflozin. BP • An average reduction in BP with canagliflozin 300 mg was 5.9/2.7 mm Hg when studied with sitagliptin. • The average BP reduction was 3.3/1.8 mm Hg with canagliflozin 100 mg and 4.6/2.5 mm Hg with canagliflozin 300 mg when compared with glimepiride. • Symptomatic hypotension can occur with canagliflozin in patients with impaired renal function, older adults, and patients on diuretics or other antihypertensive agents. LDL cholesterol • LDL cholesterol increased in a dose-dependent manner, but was balanced by an increase in HDL cholesterol. • More subjects treated with canagliflozin than sitagliptin showed changes in HDL cholesterol (+7.6% versus +0.6%) and LDL cholesterol (+11.7% versus +5.2%) concentrations. Urinary tract infection • Rates of urinary tract infections (6% versus 5%) and pollakiuria (3% versus