Glycosuria used to be a sign of uncontrolled diabetes and was something to be corrected, not a therapeutic mechanism. But now we have a new class of drugs that lower plasma glucose levels by increasing the renal excretion of glucose.
Here, we will review canagliflozin, the first in a new class of drugs for type 2 diabetes: how it works, who is a candidate for it, and what to watch out for.
THE NEED FOR NEW DIABETES DRUGS
Diabetes mellitus affects more than 25.8 million people in the United States—8.3% of the population—and this staggering number is rising.1 Among US residents age 65 and older, more than 10.9 million (26.9%) have diabetes.1 People with uncontrolled diabetes are at risk of microvascular complications such as retinopathy, nephropathy, and neuropathy, as well as cardiovascular disease. Diabetes is the leading cause of blindness, chronic kidney disease, and nontraumatic lower-limb amputation in the United States.1
Type 2 diabetes accounts for more than 90% of cases of diabetes in the United States, Europe, and Canada.2 It is characterized by insulin resistance, decreased beta-cell function, and progressive beta-cell decline.3
Current American Diabetes Association guidelines for the treatment of diabetes recommend a hemoglobin A1c target of less than 7.0%.4 Initial management includes lifestyle modifications such as changes in diet and an increase in exercise, as well as consideration of metformin treatment at the same time. If glucose levels remain uncontrolled despite these efforts, other drugs should be added.
A number of oral and injectable antihyperglycemic drugs are available to help achieve this goal, though none is without risk of adverse effects. Those available up to now include metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, gliptins, glucagon-like peptide-1 agonists, amylin analogues, colesevelam, dopamine agonists, and insulin.5 Most of the available antihyperglycemics target the liver, pancreas, gut, and muscle to improve insulin sensitivity, reduce insulin resistance, or stimulate insulin secretion.
Despite the abundance of agents, type 2 diabetes remains uncontrolled in many patients. Only 57.1% of participants with previously diagnosed diabetes in the 2003–2006 National Health and Nutrition Examination Survey were at the hemoglobin A1c goal of less than 7.0%.6 Possible reasons for failure include adverse effects such as hypoglycemia, weight gain, and gastrointestinal symptoms resulting in discontinued use, nonadherence to the prescribed regimen, and failure to increase the dosage or to add additional agents, including insulin, to optimize glycemic control as beta-cell function declines over time.
HOW THE KIDNEYS HANDLE GLUCOSE
In the kidney, glucose is filtered in the glomerulus and then is reabsorbed in the proximal tubule. Normally, the filtered glucose is all reabsorbed unless the glucose load exceeds the kidney’s absorptive capacity. Membrane proteins called sodium-glucose cotransporters reabsorb glucose at the proximal tubule and return it into the peripheral circulation. Glucose enters the tubular epithelial cell with sodium by passive cotransport via the sodiumglucose cotransporters, and then exits on the other side via the glucose transporter GLUT in the basolateral membrane.
Two sodium-glucose transporters that act in the proximal tubule of the kidney have been identified: SGLT1 and SGLT2. SGLT2 reabsorbs most of the glucose in the early segment of the proximal tubule, while SLGT1 reabsorbs the remaining glucose at the distal end.7 SGLT2 is responsible for more than 90% of renal tubular reabsorption of glucose and is found only in the proximal tubule, whereas SGLT1 is found mainly in the gastrointestinal tract.8
Patients with type 2 diabetes have a higher capacity for glucose reabsorption in the proximal tubule as a result of the up-regulation of SGLT2.9
SGLT2 INHIBITORS AND TYPE 2 DIABETES
Drugs that inhibit SGLT2 block reabsorption of glucose in the proximal tubule, lowering the renal threshold for glucose and thereby increasing urinary glucose excretion and lowering the serum glucose level in patients with hyperglycemia. This mechanism of action is insulin-independent.
On March 29, 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States for the treatment of type 2 diabetes.10 However, it is not the first of its class to be introduced.
Dapagliflozin was the first SGLT2 inhibitor approved in Europe and has been available there since November 2012. However, the US Food and Drug Administration withheld its approval in the United States in January 2012 because of concerns of a possible association with cancer, specifically breast and bladder cancers, as well as possible liver injury.10 Canagliflozin does not appear to share this risk.
Several other SGLT2 inhibitors may soon be available. Empagliflozin is in phase III trials, and the manufacturer has filed for approval in the United States. Ipragliflozin is awaiting approval in Japan.