AT ER I A EDIC A Volume 2, Issue 2

July 2013

of action recently granted an FDA-approved indication for the treatment of T2DM. This article will review canagliflozin’s mechanism of action, pharmacologic profile, safety, and efficacy in patients with T2DM.

Canagliflozin (Invokana®): A Novel Agent for the Treatment of Type 2 Diabetes

PHARMACOLOGY & PHARMACOKINETICS

Ashley Daw, PharmD

The kidneys play a vital role in glucose homeostasis through glomerular filtration and reabsorption of glucose in the proximal tubule.1,5 Glucose transport across cells of the proximal tubule is coupled with sodium transport via a cell membrane carrier protein found exclusively in the kidney, the sodium-glucose transporter 2 (SGLT2).1,6 SGLT2 is responsible for 90% of renally reabsorbed glucose.1 Glucose reabsorption occurs until renal tubular resorptive capacity is exceeded and urinary glucose excretion (UGE) occurs, also known as the renal threshold for glucose (RTG).2 This threshold occurs when the tubular glucose load exceeds 220 mg/min corresponding to a plasma glucose concentration of approximately 200 mg/dL.5 This high

T

ype 2 diabetes mellitus (T2DM) is a chronic, progressive, disease that affects 25 million Americans and 340 million people worldwide.1,2 Given the progressive nature of the disease, patients often require combinations of antihyperglycemic agents (AHAs) to achieve and maintain glycemic control. Metformin is the preferred initial pharmacologic agent for the treatment of T2DM.3 For patients unable to achieve control with metformin therapy alone, a second and eventually third AHA is often added.2 Currently available classes of AHAs include biguanides, sulfonylureas, GLP-1 receptor agonists, amylin mimetics, insulins, meglitinides, thiazolidinediones, aglucosidase inhibitors, and DPP-4 inhibitors.2,4 Each AHA has distinct benefits and risks that may help guide therapeutic choice. The 2013 American Diabetes Association guidelines recommend a patient–centered approach when considering a treatment regimen.3 Specific considerations should include efficacy, cost, potential adverse effects, weight effects, patient comorbidities, risk of hypoglycemia, as well as complementary mechanisms of action when combination therapy is employed.2,3 Many patients prefer to maximize oral agents before turning to insulin to attain glycemic control. Canagliflozin, a sodium glucose transporter 2 inhibitor, is a new oral agent with a unique mechanism

Editor’s Summary: Canagliflozin (Invokana®) Description & Indication

 Sodium glucose transporter 2 (SGLT2) inhibitor; SGLT2 is responsible for 90% of renal glucose reabsorption

 Approved for treatment of type 2 diabetes mellitus Dosing

 100–300 mg orally, once daily; contraindicated if eGFR ≤45 mL/min/1.73m2

Efficacy

 Effective as monotherapy and in combination with other oral agents and insulin

INSIDE THIS ISSUE: CANAGLIFLOZIN (INVOKANA®): A NOVEL AGENT FOR THE TREATMENT OF TYPE 2 DIABETES

 Efficacy appears similar to sulfonylureas and sitagliptin when added to metformin Safety

TREATMENT OF MENOPAUSAL VASOMOTOR SYMPTOMS: PHYTOESTROGENS AND HORMONE REPLACEMENT THERAPY

 Generally well-tolerated; urinary adverse effects are most common, including increased risk of fungal and bacterial infections, as well as increased urination

1 MATERIA MEDICA

www.ucdenver.edu/pharmacy/materiamedica

Volume 2, Issue 2

July 2013

plasma glucose concentration is often present in patients with suboptimal diabetic control. In contrast, a normal healthy adult generally filters approximately 125 mg/min.5 Decreased glucose resorption can be achieved by inhibiting the activity of SGLT2. SGLT2 inhibition results in decreased renal tubule glucose absorption, and increased glucose excretion, up to 200– 300 kcal/day.5 This direct loss of calories through the urine can lead to weight loss if not replaced or exceeded by dietary caloric intake. Caloric loss through urinary excretion is thought to contribute to the longterm weight-loss seen with SGLT2 inhibitors.8 In contrast, initial weight loss associated with SGLT2 treatment is attributed to the mild osmotic diuretic effect created by increased glucose excretion.8 The pharmacokinetics of canagliflozin are consistent between healthy subjects and those with T2DM.9 The mean absolute oral bioavailability of 300 mg canagliflozin is 65%. Food does not affect absorption, however canagliflozin should be administered prior to meals achieve post-prandial glucose lowering.8 Tmax occurs 1–2 hours after administration of 100 mg and 300 mg doses of canagliflozin in healthy subjects. The Cmax of canagliflozin is 1059–3148 ng/mL and increases in a dose-proportional manner up to doses of 1200 mg. After intravenous administration of canagliflozin, the volume of distribution is 119 L.8 Pharmacokinetic parameters of canagliflozin are listed in Table 1.

AHAs.8,9 Additionally, canagliflozin was studied in a variety of patient populations including older adults aged 55 to 80 years, those with stage 3 chronic kidney disease (CKD, eGFR ≥30 and