An abnormally high level of sugar in your urine has traditionally been a sign of uncontrolled diabetes and something to be corrected. But that notion has been turned on its head by a new class of diabetes drugs that work by increasing how much sugar patients pass in their urine.
New path to blood sugar control
To date, two of these new drugs have been approved by the U.S. Food and Drug Administration for treating type 2 diabetes. The first, canagliflozin (Invokana®), was cleared last March; the second, dapagliflozin (Farxiga®), was approved just this week.
Both drugs are so-called SGLT2 inhibitors that act by blocking the kidneys’ reabsorption of sugar, or glucose. The result is that more glucose is released in the urine and the patient’s blood glucose level goes down — a major goal of diabetes treatment.
Most other available drugs for diabetes work by targeting the liver, pancreas or gut to improve insulin sensitivity, reduce insulin resistance or stimulate insulin secretion. In contrast, SGLT2 inhibitors work completely independent of insulin.
The two new medications, which are taken by mouth in pill form, are approved for use as stand-alone drug therapy, in addition to changes in diet and increased exercise, or in combination with other drugs for diabetes. Their approvals were based on multiple clinical studies — nine for canagliflozin and 16 for dapagliflozin — showing that they effectively lowered hemoglobin A1c, a measure of average blood sugar level over the previous three months.
A surprise effect on the waistline
An added benefit is that SGLT2 inhibitors are associated with modest weight loss. For instance, patients shed from 2.8 percent to 5.7 percent of body weight in clinical studies of canagliflozin.
“The weight loss is an appealing side effect of SGLT2 inhibitors, especially in the growing population of obese individuals with type 2 diabetes,” says Cleveland Clinic endocrinologist Mary Vouyiouklis, MD. “Aside from metformin, which occasionally results in modest weight loss, other oral drugs used to treat type 2 diabetes are weight-neutral or can cause weight gain.”
Safety profile: Keeping an eye on heart effects
Another potential benefit is also a potential adverse effect: the fact that SGLT2 inhibitors have a mild diuretic effect (i.e., tend to increase urination). This results in lowering of blood pressure, which can be good for some patients who have high blood pressure but can also cause lightheadedness, dizziness or even fainting in other individuals. Dr. Vouyiouklis says caution is needed before these drugs are started in any patients at particular risk of the latter effects, such as the elderly or patients taking diuretics or multiple drugs for blood pressure.
The drugs’ other most common side effects in clinical trials — genital yeast infections and urinary tract infections — are also related to the fact that they act via the kidneys. Both drugs posed a low risk of hypoglycemia, the dangerously low blood sugar episodes associated with some diabetes therapies.
However, the new drugs were found to modestly increase levels of LDL (“bad”) cholesterol, which could be a concern because patients with diabetes are already at increased risk of heart disease. The potential for increased rates of heart attack, stroke and other cardiac events is being specifically monitored in large ongoing studies of both canagliflozin and dapagliflozin, but full results are not expected for several years.
Ongoing bladder safety scrutiny with dapagliflozin
Additionally, patients taking dapagliflozin in clinical trials showed a small increase in bladder cancer diagnoses compared with control patients. In fact, dapagliflozin was rejected for approval by the FDA two years ago because of concerns over bladder cancer and liver toxicity.
The agency’s concerns about these risks were eased by additional data from dapagliflozin’s manufacturer this time around, but the drug’s approval included a requirement that it be studied for bladder cancer risk in patients in ongoing trials as well as in new animal studies looking specifically at effects on the bladder.
Canagliflozin does not appear to be associated with bladder cancer or liver toxicity, the FDA concluded.
More agents in the pipeline
Several other SGLT2 inhibitors may soon be available as well. One of them, empagliflozin, is in late-stage studies, and the FDA is expected to decide on its approval by the end of March.
Who should get these drugs, and when?
Dr. Vouyiouklis says obese patients with type 2 diabetes and normal kidney function stand to benefit most from SGLT2 inhibitors. In general, these drugs seem to be best tolerated by patients with normal kidney function and less well tolerated by those with moderate kidney disease (they should not be used by patients with severe kidney disease). They are not approved for use by pregnant women, patients under 18 or individuals with type 1 diabetes.
“Although SGLT2 inhibitors are approved for use as single drug therapy, metformin remains my choice for first-line oral therapy,” says Dr. Vouyiouklis. “Because SGLT2 inhibitors are relatively new and their long-term effects are not yet known, I prefer to reserve them for use as add-on therapy. I believe they will be a useful addition, especially in obese patients who are seeking to lose weight.”