In March 2013 the US Food and Drug Administration (FDA) approved the drug canagliflozin (brand name Invokana) for the treatment of Type 2 diabetes. It is the first drug approved in the United States belonging to a new class of drugs called sodium-glucose cotransporter 2 (SGLT2) inhibitors. Canagliflozin can be used alone or in combination with other diabetes medicines. Canagliflozin works differently from any other medicine currently on the market for diabetes.
The discovery and development of SGLT2 inhibitors dates back to 1835, when a substance called phlorizin was isolated from the bark of an apple tree. (Extracts from apple trees and other plants were often used to treat diabetes prior to the availability of insulin.) Over the next century, phlorizin’s blood-glucose-lowering effect was studied in animals, and in 1933 it was shown to also have this effect in humans.
There’s more than one type of sodium-glucose cotransporter (SGLT) in the body. Two types in particular are responsible for absorbing glucose from the bloodstream into the body’s cells through the kidneys, and SGLT2 is responsible for 90% of this action. As a result, scientists have focused on developing a drug that selectively inhibits SGLT2.
Function of SGLT2 in the body
Normally, the kidneys filter glucose out of the bloodstream and then reabsorb it back into the bloodstream. SGLT2 is an important transporter that is responsible for this reabsorption. The drug canagliflozin is known as an SGLT2 inhibitor because it prevents SGLT2 from reabsorbing glucose; instead the extra glucose is eliminated in the urine, leading to lower blood glucose levels. SGLT2 inhibitors target the kidneys, so they work independently of the pancreas and the amount of insulin it is producing.
In addition to lowering blood glucose, canagliflozin has also been shown to lower blood pressure and promote weight loss. SGLT2 is also found in the small intestines, and preliminary evidence indicates that canagliflozin may also inhibit the intestinal absorption of glucose, therefore reducing post-meal blood glucose levels.
Results of clinical trials
Canagliflozin has been tested in over 10,000 people with Type 2 diabetes, alone and in combination with metformin, glimepiride, pioglitazone, sitagliptin, and insulin. When used alone, a 100-milligram (mg) daily dose lowered A1C by 0.77% from baseline and fasting glucose levels by 27 mg/dl, and a 300-mg dose lowered A1C by 1.03% and fasting glucose levels by 35 mg/dl. When canagliflozin was compared to the sulfonylurea glimepiride (brand name Amaryl) a 100-mg dose worked as well as glimepiride. The 300-mg dose worked better than glimepiride in lowering A1C. In people already taking metformin and a sulfonylurea, 300 mg daily of canagliflozin lowered A1C better than adding 100 mg daily of sitagliptin (Januvia).
The typical starting dose of canagliflozin is 100 mg daily, taken before the first meal of the day. For people who tolerate the drug well with few side effects and who have good kidney function, the dose can be increased to 300 mg daily if necessary. People with kidney problems should stick to the lower dose; people with severe kidney dysfunction should avoid canagliflozin entirely. Your kidney function is something you and your health-care provider should discuss before you begin taking canagliflozin, and it should be monitored while you are taking this drug, especially if it is already impaired.
There are other SGLT2 inhibitors in various stages of clinical development that have sought or will be seeking approval by the FDA. These include dapagliflozin, empagliflozin, and ipragliflozin. Dapagliflozin was not approved by the FDA in 2012 because of concerns about increased risks of bladder and breast cancer, but it was approved and is being used in Europe. So far, no increased risk of cancer has been observed with canagliflozin, but safety trials are ongoing.