(Full disclosure – I am an Advisor to Janssen pharmaceuticals that makes canagliflozin)
An FDA advisory panel last week reviewed canagliflozin, with the majority recommending approval. Canaglifozin is the first member of a new class of oral medications for type 2 diabetes–sodium-glucose co-transportor-2 (SGLT2) inhibitors–that will likely make it to the U.S. market. An earlier agent from Bristol Myers Squibb called dapagliflozin was not recommended by the advisory panel nor approved by the FDA because of a broad range of safety concerns, including a possible (although probably unlikely) signal for breast and bladder cancer. However it was approved in Europe in November of 2012.
Not a Slam-Dunk Decision
Canagliflozin was a bit more favorably received by the reviewers, but it was not a slam-dunk. The majority voted approval, but not all–the vote was 10-5. And we don’t know what the FDA will do. The reason for the divergence reflects concerns over what we may not know--an increasing fear as new drugs are reviewed.
Part of this cautiousness reflects the mixed feelings among diabetes experts about the mechanism of action of this class of agents. Simplistically, they block renal glucose reabsorption so that the patients’ glucose level is lowered through increased glycosuria. That’s doctor speak for “they pee it out.” That mechanism comes with a number of positives such as reasonably good blood glucose lowering at both modest and substantial hyperglycemia, potential use in both type 1 and 2 diabetes, and theoretical usefulness with all diabetes therapies, plus modest weight loss and a blood pressure lowering effect in part from the excess water and salt excretion. Fine.
There are also negatives. Most predictable are increased rates of urinary tract infections (modest) and genital infections (more than modest). The most prevalent is vulvovaginitis in women, although I’ve heard investigators who participated in the pre-registration clinical trials say they didn’t find it much of a problem. Balanitis also is occasionally seen especially in uncircumcised men, and that’s a bigger issue.
However, what spooked the reviewers were the unknowns. Excess urinary calcium excretion raised concerns about whether long-term bone health would be impacted. On the other hand, the good news is no cancer signal was seen. Another issue was the early-on falls in glomerular filtration rate (GFR) that then stabilizes, so the target group in terms of initial GFR is open to debate. Also, increased LDL cholesterol levels made the panel especially concerned about stroke risk, although so far there isn’t a clear CVD signal with canagliflozin. One hears lots of theory argued back and forth about the balance of the lower blood pressure and higher LDL on overall CVD risk. Still, concern over this issue was evident in the advisory panel’s 8 to 7 vote on whether canagliflozin was associated with a CVD risk profile. Eventually we can expect to get reasonably clear data on this matter since canagliflozin will have a long-term CVD safety study like all new diabetes therapies–called CANVAS that is set to report in 2015.
So on balance, some experts think canaglifozin will be the first of a useful class of agents that make intuitive sense with weight loss and efficacy in many patients and whose major side effects can be dealt with easily; others think the mechanism is silly (“we’re not treating anyone’s diabetes”) and that there may be unproven health issues.
More seriously, though, the major issue for all of us will be deciding which patients should be prescribed SGLT2s. The primary care world is already reeling from so many diabetes therapies. And a major issue with medicine generally is new therapies typically come with lots of marketing (including often direct-to-consumer), impassioned recommendations from experts (often company supported), and, sometimes, sexy mechanisms of action. Great. But they also come with high price tags and sometimes minimal advances over existing therapy.
Only Time Will Tell
So where will SGLT2s fit into this picture? Who’s the prototype patient? I don’t really know. I’ve heard it argued they will be in direct competition with DPP-4 inhibitors that have been an incredible worldwide success story. The argument is their weight loss advantage will carry the day. Maybe, but, frankly, it’s hard to know right now.
What I do know is the launch of every new drug class makes primary care providers (and specialists, frankly) question their knowledge about how to best treat type 2 diabetes. Part of that is because the diabetes specialty world has not been crystal clear in their treatment guidelines, which are more descriptive than prescriptive (I’ve made my thoughts on this topic known in earlier blogs about the 2012 ADA/EASD position statement for treating type 2 diabetes in which I referred to myself as a curmudgeon).
Tell me your opinion
So here we go again: another new class of drugs thrown into the mix for treating diabetes. I would appreciate any comments about what you think about the SGLT2 inhibitors, and my comments in general.