another FDA alert about canagliflozin/SGLT-2 inhibitors

The FDA came out with yet another warning about the SGLT-2 inhibitors (sodium glucose co-transporter-2 inhibitors) used for diabetes. this time it was about canagliflozin, used in the CANVAS study (CANagliflozin cardioVascular Assessment Study), an ongoing study, where the first results were recently presented at the European Assn for the Study of Diabetes (EASD) annual meeting (see http://www.jnj.com/news/all/phase-3-canvas-trial-show-canagliflozin-as-add-on-therapy-to-insulin-lowered-blood-sugar-levels-in-patients-with-type-2-diabetes-at-an-elevated-risk-for-cardiovascular-disease ). 1718 patients on insulin were put on canagliflozin 100mg or 300 mg, finding a 0.65 and 0.73 reduction in A1c respectively, and the previously known/expected increase in genital mycotic infections in men and women, increased urination, hypotension, and increased incidence of UTIs. But, now the FDA noted that the independent data monitoring committee for the study found an increased risk of leg and foot amputations (see http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm ), with the following: 

 An interim analysis after 4.5 years showed that over a year’s time, the risks of amputation for patients in the trial were equivalent to:

·         7 out of every 1,000 patients treated with 100 mg daily of canagliflozin

·         5 out of every 1,000 patients treated with 300 mg daily of canagliflozin

·         3 out of every 1,000 patients treated with placebo

·          

The drug monitoring board still felt that the trial continue. Therefore, the FDA recommends that we can continue to use canagliflozin but monitor patients for suggestive signs and symptoms: new pain or tenderness, sores or ulcers, or infections the patients' legs or feet

so, this brings up (yet again, for the umteenth time to those of you who have been getting these blogs for a while):

--i think we need to be very careful in adopting new drugs too quickly, unless they are real game-changers. the vast majority of new drugs, when they actually do something, usually make improvements at the fringes (ie, relatively minor additional benefits in clinical outcomes over the standard therapies). that is not to say that these drugs should never be used, just that i think using them should require a heavier burden of evidence, such as multiple confirmatory studies, with lots of different types of patients, and long enough to really assess adverse effects. too often the drugs have broad targets throughout the body (as with the DPP-4 inhibitors in diabetes), where the likelihood is higher that important disruptions in enzyme systems will manifest themselves in long-term increases in morbidity or mortality. of course, there are some real game-changers (the new hep c drugs, the early HAART drugs for HIV, statins) which so fundamentally improve morbidity/mortality that i think it is appropriate to adopt them much earlier into clinical practice

--the issue with diabetes is confounded further by the fact that the FDA is approving drugs solely based on a surrogate marker (A1C), and we certainly know of drugs that are pretty good at lowering A1C but actually increase mortality (eg rosiglitazone).

For prior blogs on SGLT-2 inhibitors, see: 

http://gmodestmedblogs.blogspot.com/2015/12/empagliflozin-good-and-bad.html​ which countered claims that the  SGLT-2 inhibitor empagliflozin is actually cardioprotective, also commenting on other adverse effects of urinary tract infections and DKA

http://gmodestmedblogs.blogspot.com/2015/05/sglt2-inhibitors-for-diabetes-may-cause.html  is a prior FDA warning about possible increases in DKA

http://gmodestmedblogs.blogspot.com/2016/01/new-dm-management-algorithm.html  is one of the new algorithms to approach diabetes, commenting on the increase in mycotic genital infections and perhaps increase in bone fractures