Canagliflozin approval ushers in new approach to T2DM

FDA’s recent approval of canagliflozin (Invokana, Janssen Pharmaceuticals) for adults with type 2 diabetes (T2DM), represents a new efficacy and unique approach to diabetes treatment, according to industry experts.

“This is the first in a new class of medications for use in diabetes,” said Richard Aguilar, MD, medical director, Diabetes Nation, LLC, and Diabetes Care Foundation, told Formulary. “It works differently than any other currently available medicines. [Canagliflozin] reduces blood glucose by acting on the kidneys as a ‘glucuretic,’ increasing the loss of glucose in the urine-what has historically been viewed as a sign of diabetes.”

Normally, explained Dr Aguilar, the kidney filters the plasma-about 3 liters-nearly 60 times a day, filtering about 180 g of glucose a day (almost 40 cubes of sugar).  Of this glucose load, 97% is reabsorbed into the bloodstream. An important transporter responsible for this reabsorption is sodium glucose co-transporter 2 (SGLT2). These transporters are located in the early portion of the proximal convoluted tubules.

“[Canagliflozin] selectively inhibits SGLT2, and as a result promotes the loss of glucose in the urine, lowering blood glucose levels in adults with type 2 diabetes,” said Dr Aguilar. “But in patients with T2DM, this system has been altered. The kidney is maladapted and reabsorbs glucose at a higher rate-increasing the renal threshold for reabsorption.”

In patients with T2DM, the kidney reabsorbs glucose at a higher rate increasing the renal threshold from a normal rate of approximately 180 mg/dL to the elevated levels of approximately 240 mg/dL and thus reabsorbs the filtered glucose load in the face of elevated plasma glucose.   

“In phase 3 clinical trials, canagliflozin not only reduced glucose in T2DM but also demonstrated additional benefits such as weight loss and blood pressure reduction, both of which are often issues that need attention in these patients,” Dr Aguilar said. “Because canagliflozin works on the kidney, it works independently of the need of or presence of insulin while demonstrating a low risk for hypoglycemia.”

“As a new, once-a-day tablet taken in the morning before meals, the novel approach of ‘spilling’ the glucose load in the urine gives primary care providers a valuable treatment too,” he added. “This is a tool that allows us to rid the excessive glucose load in the urine instead of finding tissues in the body to tuck it into such as the adipose, muscle, et cetera. Together, the glycemic benefits, blood pressure reduction, weight loss, and low risk of hypoglycemia offer a unique treatment option in the treatment of this progressive disease.”

Dr Aguilar said that he hopes that the development of this new approach for the treatment of diabetes will change the paradigm that has been in place for many years.

“Glucose in the urine may now mean removal of the excess glucose load from our patients with diabetes and not just a sign of something that is perceived as inappropriate,” he said. “Although an increase in urinary glucose demonstrated a slight increase in urinary tract infections and vaginal mycotic infections, most of these were treated with the usual standard methods of treatment by the investigators. Certainly, those patients with a history or renal impairment, the use of loop diuretics, or advanced aged ≥75 years were also at an increased risk of adverse events related to reduced intravascular volume, so caution should be used in these individuals.”

The US Centers for Disease Control and Prevention estimates that nearly 26 million Americans have diabetes, 90% to 95% of which is type 2 diabetes.

In 2016, canagliflozin is expected to have sales around $468 million, according to analysts' estimates compiled by Thomson Reuters.

For related content see Diabetes drug canagliflozin receives FDA approval