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Canagliflozin
A New Drug for Type 2

by Jennifer Goldman-Levine, PharmD, CDE, BC-ADM, FCCP

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.

Research history
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.

Pros and cons
In addition to better diabetes control, there are several other advantages to the use of canagliflozin. The glucose lost in urine by people taking canagliflozin results in a deficit of approximately 200 to 300 calories daily. In clinical trials, people taking canagliflozin lost 2% to 4% of their body weight while taking 300 mg of canagliflozin daily for six months. Another benefit identified in the clinical trials of canagliflozin was that the drug lowered systolic blood pressure between 2 mm Hg and 8 mm Hg.

Low blood glucose episodes (hypoglycemia) appear to be rare in people taking canagliflozin, though the risk does increase when canagliflozin is taken with other drugs that lower blood glucose, such as the sulfonylureas and insulin. The doses of these drugs may need to be decreased if canagliflozin is added and more frequent glucose monitoring may be necessary to avoid hypoglycemia.

Disadvantages of canagliflozin include the lack of long-term efficacy and safety data. Especially lacking are data on canagliflozin’s effect on diabetes complications, including both microvascular complications such as disease of the eyes (retinopathy), the nerves (neuropathy), or the kidneys (nephropathy) and macrovascular complications such as heart attacks and strokes. The FDA did raise concerns about an increased number of cardiovascular events (including heart attacks and strokes) during the first 30 days of one clinical trial. In this trial there were 13 events among the subjects who took canagliflozin, compared to only 1 among those who received a placebo. After the first 30 days of the trial, however, this imbalance equalized, and the FDA decided that it was mainly due to a lower-than-average rate of these events in the placebo group. There was also an increase in LDL cholesterol (low-density lipoprotein, or “bad” cholesterol) of 4% to 8% in clinical trials.

In people who have poor kidney function or who are elderly, canagliflozin may cause a lowering of blood pressure (hypotension) that causes symptoms such as dizziness, light-headedness, and fainting. This is more common in the first few months of use. Others at risk of hypotension are people who are dehydrated or who take certain blood pressure medicines such as diuretics (for example, hydrochlorothiazide or furosemide) or other blood pressure medicines that can affect the kidneys such as ACE inhibitors (lisinopril, ramipril, and others) and ARBs (losartan, valsartan, and others).

High potassium levels in the blood (hyperkalemia) can also occur in people who take canagliflozin if they have kidney problems. This is especially true in people taking drugs that may increase potassium levels (such as potassium-sparing diuretics, which include spironolactone and ACE inhibitors).

The most common adverse effects (occurring in more than 5% of people taking canagliflozin) are related to the genitourinary tract. Vaginal yeast infections occurred in approximately 10% of women who took canagliflozin. More than 5% of study participants also experienced urinary tract infections and increased frequency of urination. Adverse effects that were reported in fewer than 5% of people taking canagliflozin included fungal infections of the penis, vaginal itching, thirst, constipation, nausea, and abdominal pain.

Canagliflozin hasn’t yet been studied in people who have diabetes complications, in pregnant or breast-feeding women, or in children, and canagliflozin should not be used in these populations.

To address cardiovascular concerns and gather more information about canagliflozin’s long-term safety and efficacy, the FDA is requiring five post-marketing studies: a cardiovascular outcomes trial, a “pharmacovigilance” trial (to monitor for cancers, pancreatitis, hypersensitivity reactions, photosensitivity reactions, liver problems, and pregnancy outcomes), a bone safety study, and two pediatric studies.

Canagliflozin may not work as well in people who take rifampin (an antibiotic), phenytoin or phenobarbital (both anticonvulsants), or ritonavir (a protease inhibitor). Canagliflozin may increase the concentration of the drug digoxin (brand name Lanoxin) in the bloodstream; if you’re taking digoxin with canagliflozin, your digoxin concentration should be monitored more frequently.

Who should take it?
Until more data is available, particularly data about canagliflozin’s effect on cardiovascular health, the drug should be used as an add-on to metformin only after a person has tried other, more established diabetes drugs. If you do start taking canagliflozin, be sure to keep yourself well hydrated, and make sure your health-care provider monitors your kidney function.

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