Canagliflozin (invokana), a novel oral agent for type-2 diabetes.

The prevalence of diabetes in the U.S. has more than tripled, from 5.6 million to 20.9 million over the last three decades, with type-2 diabetes accounting for 90% to 95% of the diagnosed cases.1,2 It is projected that one in three American adults will have diabetes in 2050 if this trend continues.3 Type-2 diabetes mellitus is a progressive disease resulting from an insulin secretory defect characterized by insulin resistance and some degree of insulin deficiency.4 The prevalence of the disease is increased in obese patients, minority populations, and the elderly.2,5 Chronic long-term hyperglycemia associated with diabetes is the cause of serious complications, including blindness, kidney failure, amputations, and death.2 The economic burden associated with complications of diabetes in the U.S. was $245 billion in 2012.6 Oral hypoglycemia agents and insulin are standard therapeutic approaches, along with lifestyle modifications, to manage type-2 diabetes and to prevent complications.7,8 Despite current available therapies, about 50% of patients in the U.S. are not achieving their goals for glycosylated hemoglobin (HbA1c), blood pressure, and low-density lipoprotein-cholesterol (HDL-C) levels, as recommended by the American Diabetes Association (ADA), and 81.2% are reported to be deficient in meeting all three goals.8 Metformin (Glucophage, Bristol-Myers Squibb) is considered the initial standard of care unless it is contraindicated.7 Insulin with or without additional agents can be added to treat newly diagnosed type-2 diabetes in patients with elevated glucose or elevated HbA1c levels.7 A second oral agent—such as a glucagon-like peptide (GLP) receptor agonist, a dipeptidyl peptidase IV (DPP-4) inhibitor, a peroxisome proliferator-activated receptor (PPAR) agonist, or insulin—may be required if non-insulin monotherapy has been ineffective in achieving HbA1c goals within 3 to 6 months.7 Recent recommendations from the ADA and the European Association for the Study of Diabetes (EASD), along with the American Association of Clinical Endocrinologists (AACE), advise a patient-centered approach to management.9,10 Preferred medications are those that carry a low risk of hypoglycemia, minimize the risk of weight gain, are easy to administer, are cost-effective, and are safe to use.10 In March 2013, the FDA approved canagliflozin (Invokana, Janssen) as an adjunct to diet and exercise for adults with type-2 diabetes mellitus. This is the first oral agent in a novel class of diabetes drugs known as sodium–glucose co-transporter-2 (SGLT-2) inhibitors.11 Current research has focused on the role of the kidney in glucose homeostasis and has identified the role of SGLT-2 in mediating the reabsorption of filtered glucose in the proximal tubule.11,12 The inhibition of SGLT-2 provides a novel mechanism to lower elevated plasma glucose levels in diabetic patients.12,13