FDA Adds New Warnings on SGLT2 Inhibitors

ENDOCRINOLOGY 12.04.2015

Calls attention to ketoacidosis, UTI risks
The FDA said Friday that SGLT2 (sodium-glucose cotransporter-2) inhibitors such as empagliflozin (Jardiance), dapagliflozin (Farxiga), and canagliflozin (Invokana) will need new warnings on the risks of ketoacidosis, urinary tract infections, and other serious illnesses.

More than 70 cases of ketoacidosis have been reported to the agency, as well as 19 "life-threatening" cases of urosepsis and pyelonephritis, according to an FDA drug safety communication.

The 19 cases of serious urinary tract infections occurred only in patients treated with canagliflozin or dapagliflozin, although the FDA stopped short of saying that empagliflozin was free of such risk. Although none were fatal, four patients needed intensive care treatment and all were hospitalized. No data were available on patients’ prior history of urinary infections, and the review did not identify other factors that might predispose patients to such infections.

The SGLT2 inhibitor class of agents is used to treat both type 1 and type 2 diabetes. The drugs cause glucose to be excreted in the urine, lowering blood levels.

The agency had issued a previous warning in May about ketoacidosis with these drugs, which also include combination products such as Invokamet, Xigduo, Synjardy, and Glyxambi in which metformin or linagliptin are added.

Review of the adverse event reports disclosed that the median time between the start of SGLT2 inhibitor therapy and onset of ketoacidosis was 43 days (range 1 day to 1 year). Drug dose did not seem to be related to the risk of ketoacidosis, the agency said.

However, the review did identify some other potential risk factors. These included:

• Infection
  
• Low carbohydrate diet or reduction in overall caloric intake
  
• Reduction or discontinuation of insulin therapy
  
• Discontinuing an oral insulin secretagogue
  
• Alcohol use
  

The FDA recommended that physicians consider these risk factors before prescribing SGLT2 inhibitors and that patients taking these agents and complaining of symptoms consistent with ketoacidosis be formally evaluated. The agency also said that the drugs should be stopped if ketoacidosis is suspected.

And, when patients on these drugs have risk factors known to increase risk of ketoacidosis — such as prolonged fasting because of surgery or acute illness — clinicians should consider monitoring the patients closely or stopping the drugs altogether.

http://www.medpagetoday.com/Endocrinology/Diabetes/55035

On the same subject check this out 

5 Takeaways from the Diabetes Drugs Investigation

http://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/49196

SGLT2 inhibitors do more than just make you pee glucose. The receptors have other functions on the body so just the urinary side effects are just the tip of the iceberg. These drugs were develop from Phlorizin a naturally occurring flavonoid produced in some plants. It was believed that it caused diabetes because it make the urine sweet, later it was discovered that they just produced the effect on the kidney to diminish the re absorption of glucose.

The after marketing findings is that they increase the production of glucose by the liver, as a compensatory mechanism so they are just barely effective. Also for glucose to be in the urine, means that your glucose had to be high after eating. Just having a small effect on the A1C doesn't mean that you aren't having high hyperglycemia damage after eating before it go out in the urine. Just by the mechanism of the drug even without the side effects I believe is not really that useful.

Yeah I think Andreas Eenfeldt and Jason Fung shot themselves in the foot a bit recommending these drugs. "Low carb in a pill" sheesh, I've had UTIs and thrush, don't want to go there again. Just like DPP4 inhibitors and statins they block whole pathways other than what they are targeted on.

Sadly Eenfeldt and Fung fell for the hype from Big Pharma, long term these drugs could pose even more problems those using them are guinea pigs 

Still I would think the BDA/DUK will prefer them to the unknown long term effects of a Low Carb diet

yoly wrote:SGLT2 inhibitors do more than just make you pee glucose. The receptors have other functions on the body so just the urinary side effects are just the tip of the iceberg. These drugs were develop from Phlorizin a naturally occurring flavonoid produced in some plants. It was believed that it caused diabetes because it make the urine sweet, later it was discovered that they just produced the effect on the kidney to diminish the re absorption of glucose.

The after marketing findings is that they increase the production of glucose by the liver, as a compensatory mechanism so they are just barely effective. Also for glucose to be in the urine, means that your glucose had to be high after eating. Just having a small effect on the A1C doesn't mean that you aren't having high hyperglycemia damage after eating before it go out in the urine. Just by the mechanism of the drug even without the side effects I believe is not really that useful.

And it is a small effect on A1c at 0.36% reduction compared with a placebo, even if it came without side effects, despite all the hype it's not a cost effective option.

graham64 wrote:Sadly Eenfeldt and Fung fell for the hype from Big Pharma, long term these drugs could pose even more problems those using them are guinea pigs 

Still I would think the BDA/DUK will prefer them to the unknown long term effects of a Low Carb diet

Sadly they have both have lost focus on the priorities of diabetes. They have gone against of what research and people like Dr. Richard K. Bernstein have shown that the most important factor in diabetes is reducing high blood glucose damage. It is well researched and there should be little controversy that high blood glucose is very bad for the human body. Then there is also excess insulin, that don't have the same amount of evidence but is also well accepted is no good in excess.

Putting the emphasis in something else is a disservice to diabetics. Not all diabetes is insulin resistance at least not for many at time of diagnosis and the emphasis should not be on "curing" or "reversing" diabetes that put people in a desperate search for the magic solution. By the way I believe like Dr. Bernstein that "cure" or "reversing" is only being able to pass a glucose load test with normal glucose and insulin curve. Calorie restriction(aka fasting, bariatric surgery, Dr. Taylor diet) can help for losing weight but they are really not a "cure" for diabetes. Putting losing weight as a way to reverse diabetes is wrong and put the false idea that diabetes is all about weight loss. The only long term solution for diabetes is a LCHF diet that is sustainable and if needed the use of as little as possible of the most safe diabetic medication.

Yes agreed. You can reduce IR considerably but AFAIK you can't regrow missing beta cells. (I've read two conflicting theories there, one that genuine nondiabetics CAN increase beta cell mass with obesity or pregnancy, which diabetics can't, and that no-one can increase beta cell mass over age 30, don't know which is correct, but I strongly suspect either in different people with different genes).

"Curing" diabetes may occur if for example it is directly caused by steroids or other drugs. For everyone else CONTROL is the issue. Telling diabetics they are "cured" as many doctors now do is likely to stop them controlling it and go back face down in the hearthealthywholegrains. Likewise many doctors have been conned into believing that only A1c is useful and that "everyone" has high BG after eating. Well it may be common but is no way normal.