The New Diabetes Drug Canagliflozin (INVOKANA)

The FDA has approved a new type of drug to treat type 2 diabetes, but patients should not use the drug because it poses serious risks that outweigh its benefits.

Canagliflozin (INVOKANA) is the first member of a new family of diabetes drugs that was approved by the Food and Drug Administration (FDA) on March 29, 2013.[1] The drug, marketed in the U.S. by Janssen Pharmaceuticals Inc., is approved for use in conjunction with diet and exercise to lower blood glucose levels in patients with type 2, or non-insulin-dependent, diabetes, which is the most common type of diabetes in older Americans.[2]

The fact that a treatment is newer does not mean it is better. Canagliflozin has not been shown to offer any unique clinical benefits in comparison to several older, safer diabetes drugs. Yet it does pose serious risks that outweigh any of its benefits. Therefore, this drug is categorized as Do Not Use.

How does it work?

Canagliflozin is known as a sodium-glucose transporter 2 (SGLT2) inhibitor.[3] SGLT2 inhibitors lower blood sugar levels through a unique mechanism by causing glucose to be excreted by the kidneys into the urine and removed from the body.[4]

When blood passes through the kidneys, toxic waste products are removed, but so are substances such as glucose and sodium that are essential for life.

One vitally important function of the kidneys is reabsorbing those substances that are not waste products so they are not lost in the urine. Naturally occurring SGLT2s in the kidneys are responsible for reclaiming most of the filtered glucose and returning it to the blood. By blocking the function of these transporters, canagliflozin (a SGLT2 inhibitor) prevents some filtered glucose from being reabsorbed by the kidneys, resulting in urinary losses of glucose. As discussed below, many of the important adverse effects of canagliflozin are a direct result of the drug’s effects on glucose reabsorption by the kidneys.

Limited evidence of benefit

Like many other drugs recently approved for treating type 2 diabetes, canagliflozin was approved based solely on its effects on a so-called surrogate marker — levels of hemoglobin A1c or glycosylated hemoglobin in the blood — rather than any evidence of improvement in clinically meaningful outcomes, such as more patients surviving or fewer patients experiencing cardiovascular disease or other diabetic complications.

Glycosylated hemoglobin is a measure of how well a diabetic patient’s sugar has been controlled during the preceding two to three months. In general, physicians try to maintain patients’ hemoglobin A1c levels at 7 to 7.5 percent. Levels greater than 10 percent indicate very poorly controlled blood glucose.

The drug’s developer conducted nine randomized controlled trials of canagliflozin to determine its effectiveness. These trials lasted six to 12 months and involved a total of approximately 10,000 subjects.[5] The results of the trials demonstrated that the drug only modestly reduced hemoglobin A1c levels when used alone or in combination with other oral diabetes medications.[6] For example, for seven trials comparing canagliflozin to a placebo, the average hemoglobin A1c levels decreased from baseline before treatment with the drug by 0.29 to 0.91 percent for subjects receiving the 100 mg dose and by 0.42 to 1.16 percent for subjects receiving the 300 mg dose.[7]

What ultimately matters to patients with diabetes, however, is whether the treatment improves survival or reduces diabetic complications, the most important being cardiovascular disease (such as heart attacks and strokes), kidney failure and diabetic retinopathy, which can lead to blindness. Eight of the nine randomized controlled trials evaluating canagliflozin were not designed to measure any such clinically meaningful results, and the one trial designed to evaluate adverse cardiovascular outcomes actually suggested worse cardiovascular outcomes in the subjects who received canagliflozin in comparison to those receiving other FDA-approved diabetes drugs.

Treatment with canagliflozin was associated with small, dose-dependent decreases in body weight and systolic blood pressure.[8] However, there is no evidence from the clinical trials that these effects translated into any improvement in clinical outcomes.

Safety risks, particularly with geriatric use

Public Citizen’s Health Research Group testified before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on Jan. 10, 2013, strongly opposing approval of canagliflozin because of multiple serious safety concerns and lack of evidence for any clinically meaningful benefit.[9] These concerns, identified during clinical trials of the drug, apply particularly to the geriatric population. Many of the adverse events observed with the drug are completely expected given its mechanism of action.

Volume depletion, hypotension and impaired kidney function

Canagliflozin causes osmotic diuresis, which means increased urination as body fluids accompany the increased loss of glucose.[10] This in turn can cause a cascade of adverse events, beginning with volume depletion or dehydration and progressing to low blood pressure, dizziness, falls, renal impairment and adverse cardiovascular events.

Individuals most susceptible to the osmotic diuretic effects of canagliflozin and related complications include patients who have moderately impaired baseline kidney function, are age 75 or older, and are taking potent loop diuretics (for example, furosemide [LASIX]).[11]

Patients who develop volume depletion due to canagliflozin may develop dry mouth, thirst and polydipsia (more frequent intake of fluids).[12] They are also more likely to experience hypotension (abnormally low blood pressure), orthostatic hypotension (drop in blood pressure when standing up) and dizziness upon standing.[13] Drops in blood pressure and dizziness upon standing may predispose patients to falls and serious injuries such as hip fractures. Older patients and patients with diabetic neuropathy are more susceptible to such side effects.

Declines in renal function were also seen in patients exposed to canagliflozin during the randomized controlled trials of the drug. Patients exposed to the highest doses of the drug were most likely to experience this adverse effect. The declines in renal function occurred very soon after starting the drug and were more likely to persist in patients who had abnormal renal function prior to starting the drug.[14] Because renal function gradually declines as people get older, geriatric patients are at greater risk of experiencing the adverse kidney effects of canagliflozin.

Possible increased cardiovascular risk

Several pieces of evidence from the randomized controlled trials of canagliflozin suggest that the drug may increase the risk of adverse cardiovascular events. First, an analysis of serious cardiovascular adverse events from all nine randomized controlled trials combined showed a trend toward a higher incidence of stroke in subjects treated with canagliflozin compared to control subjects treated with a placebo or other diabetes drugs.[15] Although the difference was not statistically significant,[16] the FDA medical officer reviewing canagliflozin noted that “most of the observed strokes were ischemic, which is a concern since canagliflozin can cause volume depletion and hemoconcentration [increased concentration of red cells in the bloodstream due to dehydration].”[17] Both of these factors highlighted by the medical reviewer could contribute to an increased stroke risk.

Further reason for concern was provided by one of the nine randomized controlled trials that was specifically designed to evaluate cardiovascular outcomes. To increase the chances for detecting a cardiovascular safety signal associated with canagliflozin use, only patients with a known history of cardiovascular disease or significant risk factors for cardiovascular disease were enrolled in the trial.[18] Subjects were randomly assigned to receive either canagliflozin or placebo.[19] Data from this trial showed that during the first 30 days after randomization, 13 subjects in the canagliflozin group (0.45 percent) experienced a serious adverse cardiovascular event compared to only one subject in the placebo group (0.07 percent).[20] Given the small number of these adverse events, the results were not deemed statistically significant.[21] However, the FDA medical reviewer again highlighted reasons for concern about these results, noting:

We need to consider that the hemodynamic effect of canagliflozin is almost immediate, which was reflected in changes in blood pressure, electrolytes, renal function, as well as increased incidence of volume depletion events with canagliflozin that appear to be related to this hemodynamic changes [sic] and occur within 6 weeks of initiating canagliflozin.[22]

Such comments are an acknowledgement that there are biologically plausible reasons for why the canagliflozin may increase the risk of stroke, heart attack and other serious adverse cardiovascular events shortly after starting the drug.

Canagliflozin also causes increases in LDL (“bad”) cholesterol, which may increase cardiovascular disease risk with long-term use of the drug.[23]

Genital fungal infections

Canagliflozin was found to cause a significant increase in the incidence of genital fungal infections in both women and men. Among women enrolled in the placebo-controlled randomized controlled trials, those receiving canagliflozin had more than a fourfold higher incidence of genital fungal infections, such as yeast vaginitis, than those receiving placebo.[24] Men receiving the drug had more than a six- to sevenfold greater incidence of genital fungal infections.[25] This increase in fungal infection is undoubtedly related to the presence of glucose in the urine, which promotes growth of fungal organisms and bacteria.

Important interaction with the cardiac drug digoxin

One clinically significant drug interaction for canagliflozin occurs with digoxin [LANOXIN], a drug used to treat heart failure and to control the heart rate in patients with atrial fibrillation, an abnormal heart rhythm. Canagliflozin increases blood levels of digoxin. Patients taking both drugs should have blood levels of digoxin monitored to avoid digoxin toxicity.[26]

What You Can Do

You should avoid taking canagliflozin if you are not taking it currently. If you are taking the drug, you should consult your physician about switching to equally effective and safer drugs for type 2 diabetes. Exercise and diet are often instrumental in controlling blood sugar levels.

Consumers may report serious adverse events to the FDA’s MedWatch Adverse Event Reporting program:

Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
Fax: (800) FDA-0178
Phone: (800) FDA-1088

References

[1] Food and Drug Administration. NDA approval letter for Invokana. March 29, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/204042Orig1s000ltr.pdf. Accessed November 26, 2013.

[2] Janssen Pharmaceuticals, Inc. Drug label for INVOKANA (canagliflozin). March 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204042s000lbl.pdf. Accessed November 26, 2013.

[3] Ibid.

[4] Kwon HJ. FDA Medical review(s) for new drug application 204042 for canagloflozin. February 8, 2013. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf. Accessed November 26, 2013.

[5] Ibid.

[6] Ibid.

[7] Ibid.

[8] Ibid.

[9] Wolfe S. Testimony before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. January 10, 2013. http://www.citizen.org/documents/2091.pdf. Accessed November 26, 2013.

[10] Ibid.

[11] Ibid.

[12] Ibid.

[13] Ibid.

[14] Ibid.

[15] Ibid.

[16] Ibid.

[17] Ibid.

[18] Ibid.

[19] Ibid.

[20] Ibid.

[21] Ibid.

[22] Ibid.

[23] Ibid.

[24] Ibid.

[25] Ibid.

[26] Janssen Pharmaceuticals, Inc. Drug label for INVOKANA (canagliflozin). March 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204042s000lbl.pdf. Accessed November 26, 2013.