By Annette M. Boyle
SAN DIEGO – The Food and Drug Administration’s (FDA) recent approval of canagliflozin might soon offer new treatment options for the more than one million VA patients with diabetes.
“This is definitely not a ‘me too’ drug,” said Candis Morello, PharmD, CDE, FCSHP, director, Diabetes Intense Medical Management Clinic, Veterans Affairs San Diego Healthcare System, and associate professor of clinical pharmacy, University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences.
“It’s an additional treatment option and a very complementary medication, particularly with metformin. Some new efficacy studies show that it significantly reduces HbA1c and promotes weight loss, and other studies have indicated that it lowers blood pressure as well, which is definitely a problem for people with diabetes,” Morello told U.S. Medicine. “It also doesn’t cause hypoglycemia, which we want to avoid at all costs.”
Canagliflozin, marketed as Invokana by Johnson & Johnson’s Janssen Pharmaceuticals Inc., is the first FDA-approved therapy in the sodium-glucose co-transporter 2 (SGLT-2) inhibitor class of drugs. SGLT2 inhibitors block a protein involved in glucose reabsorption in the kidneys, allowing the body to excrete excess blood sugar in urine. Consequently, drugs in this class lower blood glucose levels and contribute to weight loss.
Last year, the FDA rejected another drug in the category, dapagliflozin, because of concerns about cancer. Dapagliflozin gained approval in Europe in November and is likely to be reconsidered by the FDA this summer. Another SGLT-2 inhibitor, empagliflozin, recently filed for FDA approval and a fourth, ipragliflozin, filed for approval in Japan.
“It’s important to have medications with multiple mechanisms of action when targeting a disease like diabetes that is caused by multiple pathophysiologic deficiencies,” Morello said. “Diabetes treatment in the VA is very patient-centered. This new drug gives us another tool to use to meet patient needs and preferences, particularly for patients who are 1% or more above goal or who want an oral rather than injectable medication.”
Safety and Effectiveness
Canagliflozin’s safety and effectiveness were evaluated in nine clinical trials involving more than 10,000 type 2 diabetics, with performance assessed as a stand-alone therapy and in combination with other therapies including metformin, sulfonylurea, pioglitazone and insulin. It is not approved for treatment of type 1 diabetes and should not be used in patients with elevated ketones in their blood or urine or in patients with impaired renal function.
Kidney function might impose a real limit on the use of the entire class of SGLT-2 drugs, as more than 35% of adult patients with diabetes have chronic kidney disease. As kidney function tends to decline over time in diabetics, SGLT-2 drugs might have less of a role in treating diabetes later in disease progression.
To monitor safety, the FDA has required five post-marketing studies for canagliflozin. The studies include a cardiovascular outcomes trial; a program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity and photosensitivity reactions, liver abnormalities and adverse pregnancy outcomes; a bone safety study; and two pediatric studies.
The biggest concern for patients, however, is likely to be more readily apparent.
“Genital infections are the most common side effect,” said Morello. “Women tend to be more inclined to yeast and bacterial infections, but, for the large percentage of our patients who are male, urogenital infections are less likely to be a problem, particularly when the medication is paired with education about the importance of good hygiene.”
In a recent randomized clinical trial published in the journal Diabetes Care, 9% of men and 15% of women developed genital infections, although researchers noted that the infections responded to usual treatment and resulted in few discontinuations. Studies have not shown whether these infections are likely to recur.1
Canagliflozin also has a diuretic effect, and prescribers should respond accordingly, Morello said.
“I’d use it with caution in our oldest veterans,” she cautioned, “because it can cause changes in plasma volume and electrolyte changes.” Those effects may lead to orthostatic or postural hypotension and increases in dizziness and falls, particularly risky for the frail elderly.
In addition, some patients may experience gastrointestinal effects. “While the SGLT-2 inhibitors are selective, they still have some effect on SGLT-1 receptors, which can cause GI upset in some patients,” Morello noted. “I think we’ll see greater specific selectivity as newer agents in the class gain approval and that will reduce their impact on the SGLT-1 receptors in the gut.”
Second or Third Line Therapy
“The current guidelines say always start with metformin. After that, I don’t see any reason why this wouldn’t be a second-line drug in the next revision of the guidelines, depending on the results of post-marketing surveillance,” Morello said.
In theory, she said, canagliflozin could even be a first-line therapy for patients who cannot tolerate metformin, though most physicians might prefer to try a more established drug initially. Recommendations from the American Association of Clinical Endocrinologists last month included SGLT-2 treatment as appropriate for first, second or third line therapy.
The 1% reduction in A1C seen with canagliflozin in studies is greater than that seen with several current second-line medications, including sitgliptin and DPP-4s.
“I recently had a patient come in who had had glucose levels above 400 for months. I started him on insulin, and he quickly dropped to goal. I’d consider adding an SGTL-2 inhibitor to the mix for someone like that,” she said.
As a third-line drug, canagliflozin could help patients on metformin and a second drug, such as sulfonylureas or pioglitazone. Many patients see declining results from combination therapies over time as their pancreatic beta cells become less responsive. For them, a once-a-day tablet might be a more palatable option than insulin injections.
Canagliflozin is priced at $8.77 per tablet, comparable with diabetes drugs in several other relatively new classes.
“I don’t mind spending a little more money to get a much better result,” added Morello. “I do wish the manufacturer had made it a little more affordable, though.”
Currently, the manufacturer is offering a savings card — information is available online at www.INVOKANACarePath.com — to significantly lower costs for patients prescribed the drug.
1 Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: A 52-week randomized trial. Diabetes Care. April 5, 2013. Published online before print.