New York, NY - To some experts, the newly licensed novel glucose-lowering drug canagliflozin (Invokana, Janssen Pharmaceuticals) is a welcome addition to the armamentarium of treatments for type 2 diabetes. For others, it's a drug with too many as-yet unanswered safety questions to overcome modest benefits. Still others fall somewhere in between. But everyone agrees that further study is essential.
The fact that two endocrinologists who were asked about the recent licensure of canagliflozin by the US Food and Drug Administration (FDA) have quite differing views about the drug is perhaps no surprise, because so did advisory committee members at the FDA hearing held in January. Two of the cardiology members of that advisory panel were also asked their thoughts on the new drug.
Chief among concerns were the unanswered questions about cardiovascular safety with canagliflozin, a topic of great interest with regard to diabetes drugs in general. Many also view some of the adverse effects with the new agents as being off-putting, particularly the increased incidence of genital fungal infections.
And while some feel the decision to approve canagliflozin was right, given the postmarketing requirements instituted, one of the endocrinologists questions this whole drive to license new diabetes drugs, wondering what value they really add. Canagliflozin, for instance, has as many adverse effects as older agents, with vastly increased costs, he observed.
Canagliflozin is the first in a new class of glucose-lowering drugs, an oral inhibitor of sodium glucose cotransporter 2 (SGLT2). Inhibition of SGLT2 reduces resorption of glucose in the kidney, resulting in increased urinary glucose excretion, with a consequent lowering of plasma glucose levels as well as weight loss.
The FDA approved canagliflozin on March 29, 2013, with the requirement that the company perform five separate postmarketing studies. Among these is the completion of the ongoing cardiovascular outcomes trial, Canagliflozin Cardiovascular Assessment Study (CANVAS), which the company is conducting to fulfill the 2008 FDA guidance regarding cardiovascular safety for investigational diabetes drugs. Final results of CANVAS, which enrolled a total of 4330 individuals with CVD or at high risk for it, are not expected until 2015.
Data from CANVAS submitted to the FDA and reviewed at the January hearing suggested that, overall, canagliflozin was not associated with an increased risk for cardiovascular events. However, there was a 46% elevated risk for stroke, particularly within the first 30 days of treatment, although the numbers were small.
Dr Sanjay Kaul (David Geffen School of Medicine at the University of California, Los Angeles), one of the cardiologists who served as a temporary voting member on the FDA's Endocrinologic and Metabolic Drugs Advisory Committee at the January hearing, said in an interview that he questioned whether the company's use of interim data from CANVAS to seek approval for canagliflozin and then continuing the same trial postapproval was actually in compliance with the 2008 FDA guidance, which calls for completed trials.
"They're using one set of end points for crossing the first hurdle, the preapproval study, then using an efficacy end point for postapproval. Technically speaking, there are some statistical issues with that," he said.
"To me, the most interesting thing was to see how FDA is interpreting its own guidance documents. That was an interesting twist . . . because the guidance was not very clear on that," noted Kaul.
One problem, he explained, is that the reporting of the interim data to support licensure partially unblinded CANVAS for both patients and investigators, which could affect the ultimate results. "Partial unblinding of the data while the trial is ongoing always challenges reliable and unbiased estimate of a trial," he noted.
Kaul ultimately voted in favor of approving canagliflozin, "but my vote came with many caveats," he said. Among his concerns is a lack of sufficient data on risk among patients with moderate to severe renal impairment. And, from a patient perspective, he believes that the four- to sevenfold increased risk for genital mycotic infections seen with canagliflozin is what will "make or break" the drug once it's on the market. Although treatable, "It's not appealing. That's what I think…we'll see."
Nonetheless, he said, "I think the FDA did the right thing and has demanded an array of postapproval studies, which I think is appropriate."
While canagliflozin is the first SGLT2 inhibitor to reach the market in the US, another drug in this class, dapagliflozin (Forxiga, Bristol-Myers Squibb/AstraZeneca), is already available in Europe; it was approved there in November 2012. The FDA denied approval of dapagliflozin in January 2012 because of concerns about a cancer signal. Canagliflozin, which has also been submitted for approval in the European Union, does not appear to share that risk, with no signal for an increase in malignancy in about 8000 person-years of exposure.
A third SGLT2 inhibitor, ipragliflozin (Astellas Pharma) has been filed for marketing approval in Japan, and a fourth, empagliflozin (Eli Lilly/Boehringer Ingelheim), is in phase 3 trials and has just been filed for approval in the United States.Now that it is okayed, some CV advice while waiting for data
The other cardiologist who served as a temporary voting member on the FDA advisory panel for canagliflozin, Dr William R Hiatt (University of Colorado School of Medicine, Aurora), had voted against approval. But he said that he did so because he saw his responsibility on the panel differently from that of noncardiologist members.
"I felt that, representing the cardiovascular side of the equation, I should vote no to make sure there's not 100% agreement that this is a good drug to be put on the market," said Hiatt. "I actually think that discussion is more important than the voting, but the voting does force you to declare yourself. I feel that if you walk away with 100% voting to put it on the market, that sends a message to clinicians that this drug is okay. I'm not sure yet it's 100% okay, so I voted no," he said.
But now that canagliflozin has been licensed, Hiatt offered some advice regarding the first 30 days of use, during which he attributes the elevated risk [of stroke] found by the FDA analysis to an acute osmotic diuretic effect that could be destabilizing in a patient with underlying coronary artery disease.
"Typically with osmotic diuretics, or any diuretic after you've been on it for a while, your body readjusts to it and you reach new equilibrium, in which case the risk might go down," he observed.
So he would advise patients to drink plenty of water in the first 30 days of treatment and to seek medical advice if they experience worsening angina or any other symptom suggestive of a cardiac problem. After the first month, Hiatt said he'd be less concerned but still cautious in patients with underlying cardiovascular disease.
And of course, he is looking to the postmarketing data for more answers. "The more events one can look at across the development program, the better. It would certainly mitigate any lingering concern. "Canagliflozin vs GLP-1 agonists and DPP-4 blockers
From the perspective of diabetes, endocrinologist Dr Alan J Garber (Baylor College of Medicine, Houston, TX), who was not part of the FDA advisory panel, said the new drug provides a novel treatment choice.
"Canagliflozin provides another therapeutic option for patients with type 2 diabetes. This option is beneficial since it's not dependent on endogenous insulin secretion, has no proclivity for excess risk of hypoglycemia, and is generally associated with modest weight reduction," he said in an interview.
Garber said at this point he envisions the use of canagliflozin as a second-line agent following metformin and lifestyle modification or for patients who can't tolerate metformin.
"At the present time, the only other category of agents about which we can get enthusiastic are the incretins—the [glucagonlike peptide 1] GLP-1 agonists and [dipeptidyl peptidase-4] DPP-4 inhibitors—I would see an SGLT2 inhibitor competing in that same space," noted Garber. As for potential risk, he said he anticipates more definitive data will be available two to four years after marketing. "You have to treat the diabetes with something. Regardless of what it is you choose, all of those 'somethings' are associated with adverse events. . . . There's no medication that's free of any concern, but there is of course lots of concern about untreated diabetes. So you just have to find the best medication that suits the patient's profile and try to make a good match that way."Are all these newer diabetes drugs really warranted?
Another endocrinologist not involved with the FDA panel, Dr David M Nathan (Harvard Medical School, Boston, MA) has a different take, however. Noting canagliflozin's "fairly weak" glucose-lowering potential (0.62% and 0.77% reductions in HbA1c, for 100 mg and 300 mg, respectively, when combined with metformin) and its safety concerns, he said that he is not convinced of its merits.
"The FDA operates according to its rules and guidelines. . . . I can't complain about the process, but I do remain generally concerned regarding this flooding of the market with diabetes drugs that really are not substantially better, and in some ways worse, than the older, less expensive, generic drugs that are available," he observed.
And although weight loss is another potential benefit of canagliflozin, "the weight loss is probably related to a bit of dehydration as well as potentially a slight decrease in calorie absorption because you're losing it in the urine. Old-fashioned poorly controlled diabetes did the same thing," said Nathan,
And although the 3- to 5-mm-Hg drop in blood pressure seen with canagliflozin might be considered "value added," he said this is also likely a result of the dehydration and loss of sodium. Other downsides are the fungal-infection risk, the uncertainty regarding cardiovascular end points, and the cost, among other things. "So, this is not a drug I'd be enthusiastic about," Nathan said
In general, he said, "I certainly encourage the development of new drugs, but I wonder at what point we will think more critically about the value added and the value subtracted. . . . Every drug has warts. Sulfonylureas, metformin, and insulin all have problems. The question is how much we gain by having this huge number of choices.
"The cost of diabetes medication is going up more quickly than for the treatment of any other disease. It's incredibly expensive, and at some point we have to start watching the bottom line," he concluded.
| Kaul disclosed that he owns "very modest" stocks in Johnson & Johnson and is a consultant for Novo-Nordisk. Garber is a consultant to, on the advisory board of, and/or on the speaker's bureau for Novo Nordisk, Merck, Halozyme, Janssen, Takeda, Vivus, Santarus, Tethys Bioscience, Viking Therapeutics, and Eisai. Hiatt and Nathan have reported no relevant financial relationships.
Heartwire from Medscape © 2013
Cite this: Experts welcome canagliflozin approval, but questions remain - Medscape - Apr 19, 2013.