SGLT2 inhibitors: updated advice on the risk of diabetic ketoacidosis

[ickihun]

His warning is specific for keto type diets, but the referenced case study just specifies a low carb diet. I would suggest that both are relevant to this warning. I believe that ketoacidosis has also been reported with other diets too, and I am not sure that ketosis elevates the risk to any greater degree. It is the action of these meds that is at fault since they interfere with the kidney filtration and excretion pathway. which in turn leads to a buildup of waste products,

These drugs have been tested for kidney health safety. Just recently it was declared safe.
Only after having enough human data.... through usage (human guinea pigs). Humf!
The thrush I experienced was horrendous after just get rid of 2yrs of it too.
I tried numerous ways of tolerating it. The thrush luckily was enough of a warning sign that my body was stressed.. on it.
My meter showed 7s steadily and remarkably and on very little insulin, I even thought at one stage with metformin being reintroduced I could have stopped insulin but Wham! The thrush stopped me in my tracks.... even on 2ltr at least if water throughout the day. It seemed the more I drank the worse the thrush!

I feel I was close to DKA on canagliflozin but was never tested but luckily as I was on insulin therapy so I treated bgs appropriately on stopping this drug. I'm very confident with insulin medication. Not everyone would be so lucky.

DKA affects the muscles too. My muscle strength has never been the same, nor bone and joint strength either.
I've exceeded limitations on suing about canagliflozin damage but in all honesty I'd never sue my nhs endo specialist anyway. He is very very good at his job at fighting type2 diabetes. I support him. He has done me proud in keeping me safe. I couldnt ask for a better endo for my hormonal complications! They are thin on the ground.

 

[ringi]

virtahealth covered this in their lasted Facebook Q&A, they don't see any real imcreases risk from SGLT2 inhibitors with low carb. But they do try to stop them quickly as they are expensive in the USA and they question if they give any benefit to people who are keeping to a strict low carb diet.

They also pointed out that as everyone is testing their keytons each day with a doctor monitoring the results (with the help of AI) that if keytones did start going too high they would pick it up quickly before any real long term harm was done.

Personally I still expect the issue is people with a low insulin production being given SGLT2 inhibitors, but as fasting inslin level is not tested as standard we don't know. (I think virtahealth does the test) Remember that both low carb and SGLT2 reduce blood inslin levels and it is very low inslin levels that result in DKA not high BG.

 

[ickihun]

virtahealth covered this in their lasted Facebook Q&A, they don't see any real imcreases risk from SGLT2 inhibitors with low carb. But they do try to stop them quickly as they are expensive in the USA and they question if they give any benefit to people who are keeping to a strict low carb diet.

They also pointed out that as everyone is testing their keytons each day with a doctor monitoring the results (with the help of AI) that if keytones did start going too high they would pick it up quickly before any real long term harm was done.

Personally I still expect the issue is people with a low insulin production being given SGLT2 inhibitors, but as fasting inslin level is not tested as standard we don't know. (I think virtahealth does the test) Remember that both low carb and SGLT2 reduce blood inslin levels and it is very low inslin levels that result in DKA not high BG.

Thats right about absent insulin results in DKA and that's why I feel lucky I was able to hugely increase my insulin quickly on stopping canagliflozin. Phew!

 

[Oldvatr]

Thats right about absent insulin results in DKA and that's why I feel lucky I was able to hugely increase my insulin quickly on stopping canagliflozin. Phew!

One of the bonus points for these drugs was that their operation was supposed to be self regulating, i.e. they dropped bgl by extracting glucose via the kidneys, but did not operate when bgl is below 'normal' levels. They were supposed to be safe because of this, so it is not clear what the mechanism causing DKA is. Unlikely to be insulin dropping off the scale if the reports of DKA happening with bgl still in the 7-10 mmol/l range are true. There must be something else happening instead.

 

[ickihun]

One of the bonus points for these drugs was that their operation was supposed to be self regulating, i.e. they dropped bgl by extracting glucose via the kidneys, but did not operate when bgl is below 'normal' levels. They were supposed to be safe because of this, so it is not clear what the mechanism causing DKA is. Unlikely to be insulin dropping off the scale if the reports of DKA happening with bgl still in the 7-10 mmol/l range are true. There must be something else happening instead.

I think meter reading blood doesn't give a true reading from blood of before kidneys have extracted the bulk of glucose. So a 7.0 on our meter may be a 11.0, or higher in some cases, circulating until extraction. Even circulating kidneys. I know kidney stones haven't been ruled out, just kidney disease.

 

[ringi]

Unlikely to be insulin dropping off the scale if the reports of DKA happening with bgl still in the 7-10 mmol/l range are true. There must be something else happening instead.

A sglt2 inhiberitor can at times keep BG in that sort of range even when there is no inslin in the blood. (Regardless of low carb, but clearly more likely with low carb.) Maybe everyone on sglt2 should be issued with blood keytone meters with daily checking.

 

[Oldvatr]

I think meter reading blood doesn't give a true reading from blood of before kidneys have extracted the bulk of glucose. So a 7.0 on our meter may be a 11.0, or higher in some cases, circulating until extraction. Even circulating kidneys. I know kidney stones haven't been ruled out , just kidney disease.

Sorry, @ickihun I am nor sure how your reply here relates to DKA. The classic Diabetic DKA is usually a result of there being insufficient insulin around to allow glucose to pass into the mitrochondia to be used, and the body burns fat instead to survive thus producing ketones in abundance. The classic DKA is associated with high (>20 mmol/l) bgl readings and severe ketobreathe (pear drops). Contrary to that SGLT-2 DKA differs in that it has been observed when bgl levels are in the 10 -15 mmol.l range, and so present a hazard in that ER staff may not realise the symptoms, and provide the wrong treatment.

So Classic DKA is due to loss of insulin (normally associated with Insulin dependants) or very high Insulin Resistance (e.g. T2D - rare event), but SGLT-2 DKA may only present ketobreath as a clue. I am not sure how a keto diet would lead to higher risk with SGLT-2 since it should not reduce insulin production or increase IR. Anyway, either of those events would show as high bgl levels and classic DKA symptoms, which is why I say there must be some other mechanism coming into play with SGLT-2 meds.

I suggested an interference with kidney function in that maybe the SGLT-2 med is causing them to stop filtering not just glucose as designed, but also other waste products that should normally be excreted in the urine. such as ketones.

For some reason DKA due to SGLT-2 is causing a backup of ketone byproducts in a big way leading to ketoacidosis (which is not the same as normal ketogenic waste due to diet restrictions or heavy exercise or fasting) An alternatice hypothesis is that SGLT-2 causes the kidneys to flush insulin instead, but I suspect that would lead to high bgl readings again, but then thinking about it on the fly, leaching insulin while having low bgl for keto may only cause a small rise in bgl i.e. to 10 -15 mmol/l as reported.

 

[Oldvatr]

A sglt2 inhiberitor can at times keep BG in that sort of range even when there is no inslin in the blood. (Regardless of low carb, but clearly more likely with low carb.) Maybe everyone on sglt2 should be issued with blood keytone meters with daily checking.

Yes, but the OP was specific about not using keto diet. Ketosis requires low bgl to happen. I am not aware of anyone having SGLT-2 DKA happen while bgl levels are that low. The difficulty I see is that SGLT-2 DKA occurs in the midrange which is not the normal DKA symptom. Also the acidosis is happening with lowish bgl, which is normally where we expect insulin to be working and either burning glucose or storing it away. If neither of these is occurring then the bgl levels climb into the stratosphere. and would not hang around in midrange for long.

 

[ickihun]

Yes, but the OP was specific about not using keto diet. Ketosis requires low bgl to happen. I am not aware of anyone having SGLT-2 DKA happen while bgl levels are that low. The difficulty I see is that SGLT-2 DKA occurs in the midrange which is not the normal DKA symptom. Also the acidosis is happening with lowish bgl, which is normally where we expect insulin to be working and either burning glucose or storing it away. If neither of these is occurring then the bgl levels climb into the stratosphere. and would not hang around in midrange for long.

Mid-range..... By a Mid-range hba1c and Mid-range finger prick!

I'm saying the testing methods don't work well on these drugs due to our human circulatory system. So dka is close for some on e.g canagliflozin in fact but meter and circulatory blood is saying mid-range!
These testing messures aren't accurate for these meds! Because of their change to circulatory blood glucose. It's forced out instead on staying in deoxigenised circulatory blood, which tests mid-range but glucose has already been feeding nerves/muscles etc... first before being filtered out by our kidneys????
The gut absorbs nutrients first.... Well before kidneys get a look in.

 

[ickihun]

I know because in times of vomiting the sugar can still have been absorbed into the system before full stomach contents gets emptied.
True. If stomach not emptied quick enough.

 

[Oldvatr]

Mid-range..... By a Mid-range hba1c and Mid-range finger prick!

I'm saying the testing methods don't work well on these drugs due to our human circulatory system. So dka is close for some on e.g canagliflozin in fact but meter and circulatory blood is saying mid-range!
These testing messures aren't accurate for these meds! Because of their change to circulatory blood glucose. It's forced out instead on staying in deoxigenised circulatory blood, which tests mid-range but glucose has already been feeding nerves/muscles etc... first before being filtered out by our kidneys????
The gut absorbs nutrients first.... Well before kidneys get a look in.

DKA is an Acute condition requiring immediate arttention, so it must be finger prick test or CGM type of device. A venous blood test can be assayed in a specialist lab within a few hours, but in a doctors surgery or hospital ER there is probably no immediate access to a YSI plasma analyser or a gas chromatograph facility, and bloods will have to be sent away to a lab for analysis. That route is more accurate than a fingerprick test meter, but accuracy will not help someone in DKA.

It is true that there will be delays in the circulatory system that may give false results for a spot check of rising or falling bgl, which is why hospitals will repeat on a few occasions since it takes about one minute for a cycle of the blood to complete and settle down. So in the setting of an ER admission then they should not use just one result to make a diagnosis.

You say that the glucose will already be in the cells doing its stuff. This is fine, and is what normally happens. DKA occurs when the glucose is not able to get into the cells at all, and remains in the blood stream and bgl rises alarmingly. Something linked to SGLT-2 is stopping the glucose from being used normally. What is different about this version of DKA is that bgl levels do not rise into the high ranges, but remain at what would usually be regarded as a 'safe' i.e. non emergency level.

I would also point out that the kidney filtering out of glucose is not an immediate effect, and there is a delay. Bgl does not drop like a stone falling off cliff, but happens over hours. So I would be surprised if SGLT-2 DKA was happening because of a delay problem, unless it is the Stage 1 Insulin Response being suppressed following a meal. However,this means DKA by medication would self correct when the body used up the med, and ER would not be needed. However, this may need further study to evaluate.

I will just add that I have never myself experienced a DKA event, but I have had readings that my meter was unable to display except for (HI or KETONE) warnings. so DKA is not the cause of high bgl, but high bgl is a sign of possible DKA. Since I am not Insulin Dependant then it is clear that my body was still producing some of its own insulin, so I recovered naurally without intervention. In fact I felt great when my bgl was above 32 mmol/l and had no indication that I was in danger until I started self monitoring again and saw my meter readings. I was running on high octane glucose and fumes.

Edit to add: found this discussion doc on the problem. It too suggests that SGLT2 meds can decrease kidney filtering out of ketone products.
https://academic.oup.com/jcem/article/100/8/2849/2836082

Apparently a recent Japanese study demonstrated that SGLT2 med increased Glucagon, which in turn promoted extra lipidolysis thus leading to higher ketone levels being present, regardless of diet.

But a LC diet will add its own ketone bodies to the mix, thus amplifying the effect. Low insulin levels also makes things worse. So any Insulin users on LC need to be aware that reducing insulin bolus due to low carb may increase the risk when used in conjunction with these meds. Thus this effect has been identified as being a Class problem caused by this med type.

It is already established that this med type is not licenced for use with T1D in the USA, but in UK it is not restricted in this aspect (the restriction was lifted in May 2017) and it is also now being promoted for protecting the kidneys in T1D by NICE. Make of that what you will.......

 

[ickihun]

DKA is an Acute condition requiring immediate arttention, so it must be finger prick test or CGM type of device. A venous blood test can be assayed in a specialist lab within a few hours, but in a doctors surgery or hospital ER there is probably no immediate access to a YSI plasma analyser or a gas chromatograph facility, and bloods will have to be sent away to a lab for analysis. That route is more accurate than a fingerprick test meter, but accuracy will not help someone in DKA.

It is true that there will be delays in the circulatory system that may give false results for a spot check of rising or falling bgl, which is why hospitals will repeat on a few occasions since it takes about one minute for a cycle of the blood to complete and settle down. So in the setting of an ER admission then they should not use just one result to make a diagnosis.

You say that the glucose will already be in the cells doing its stuff. This is fine, and is what normally happens. DKA occurs when the glucose is not able to get into the cells at all, and remains in the blood stream and bgl rises alarmingly. Something linked to SGLT-2 is stopping the glucose from being used normally. What is different about this version of DKA is that bgl levels do not rise into the high ranges, but remain at what would usually be regarded as a 'safe' i.e. non emergency level.

I would also point out that the kidney filtering out of glucose is not an immediate effect, and there is a delay. Bgl does not drop like a stone falling off cliff, but happens over hours. So I would be surprised if SGLT-2 DKA was happening because of a delay problem, unless it is the Stage 1 Insulin Response being suppressed following a meal. However,this means DKA by medication would self correct when the body used up the med, and ER would not be needed. However, this may need further study to evaluate.

I will just add that I have never myself experienced a DKA event, but I have had readings that my meter was unable to display except for (HI or KETONE) warnings. so DKA is not the cause of high bgl, but high bgl is a sign of possible DKA. Since I am not Insulin Dependant then it is clear that my body was still producing some of its own insulin, so I recovered naurally without intervention. In fact I felt great when my bgl was above 32 mmol/l and had no indication that I was in danger until I started self monitoring again and saw my meter readings. I was running on high octane glucose and fumes.

Thanks @Oldvatr. I always enjoy your posts. Thanks for educating me. As you can see, I needed it.
I get knocked out on high bgs. I struggle to be aroused. I get out of bed and my muscles ache, severely and I start with palpatations..... not too much different to hypos but lethargic to the extreme and aching muscles with breathlessness, at times. I check meter then inject novarapid if high, then eat.
However I'm no longer on canagliflozin where I was vomiting too.

 

[ringi]

With high inslin resistance there other ways other then DKA to quickly die from very high BG. Few people with type1 can die from these as DKA gets them first.....

@ickihun I expect that when your BG is high your inslin is too high to put you at risk of DKA.

 

[Michele01]

I realise this is an old thread but I'm one of the 118 yellow card warnings that occurred in the UK - and I was one of the first 20 to be reported. I was newly diagnosed Type 2 and as I was having horrible side effects with Metformin, I was given Forxiga. I took it for about 3 weeks. My bg levels were fantastic. After about 2.5 weeks I started to feel like I had the worst case of 'flu ever! My husband took me to A&E because I was finding it difficult to even walk to the door. I saw an emergency doctor who was worried but as my BG levels were ok, wasn't sure what was going on. She was so worried that she insisted the ward run blood tests. It's lucky she did as it turned out I was in an advanced state of ketoacidosis. I was told had I not been admitted to ICU that night, I wouldn't have been alive the following day. For reference, I was not on a low carb diet or anything like that. Thankfully I made a full recovery but the damage had been done and I'm now insulin dependent. There is no way I would recommend this drug to anybody. I don't believe full testing has been done. The danger with this drug is that your bg levels may be exceptionally good but the damage is happening behind the scenes and if a doctor isn't on the ball, it can well be missed.

 

[Oldvatr]

I realise this is an old thread but I'm one of the 118 yellow card warnings that occurred in the UK - and I was one of the first 20 to be reported. I was newly diagnosed Type 2 and as I was having horrible side effects with Metformin, I was given Forxiga. I took it for about 3 weeks. My bg levels were fantastic. After about 2.5 weeks I started to feel like I had the worst case of 'flu ever! My husband took me to A&E because I was finding it difficult to even walk to the door. I saw an emergency doctor who was worried but as my BG levels were ok, wasn't sure what was going on. She was so worried that she insisted the ward run blood tests. It's lucky she did as it turned out I was in an advanced state of ketoacidosis. I was told had I not been admitted to ICU that night, I wouldn't have been alive the following day. For reference, I was not on a low carb diet or anything like that. Thankfully I made a full recovery but the damage had been done and I'm now insulin dependent. There is no way I would recommend this drug to anybody. I don't believe full testing has been done. The danger with this drug is that your bg levels may be exceptionally good but the damage is happening behind the scenes and if a doctor isn't on the ball, it can well be missed.

Thank you for shareing this with us here. When I started this thread, I was worried that I was crying wolf and possibly scaremongering, but there have been a few reports here from sufferers who also were not doing low carb. had low bgl levels, and were nearly missed by ER staff. So this risk is real and not to be taken lightly.

 

[ringi]

I realise this is an old thread but I'm one of the 118 yellow card warnings that occurred in the UK - and I was one of the first 20 to be reported. I was newly diagnosed Type 2 and as I was having horrible side effects with Metformin, I was given Forxiga. I took it for about 3 weeks. My bg levels were fantastic. After about 2.5 weeks I started to feel like I had the worst case of 'flu ever! My husband took me to A&E because I was finding it difficult to even walk to the door. I saw an emergency doctor who was worried but as my BG levels were ok, wasn't sure what was going on. She was so worried that she insisted the ward run blood tests. It's lucky she did as it turned out I was in an advanced state of ketoacidosis. I was told had I not been admitted to ICU that night, I wouldn't have been alive the following day. For reference, I was not on a low carb diet or anything like that. Thankfully I made a full recovery but the damage had been done and I'm now insulin dependent. There is no way I would recommend this drug to anybody. I don't believe full testing has been done. The danger with this drug is that your bg levels may be exceptionally good but the damage is happening behind the scenes and if a doctor isn't on the ball, it can well be missed.

Was your fasting inslin levels checked before you were put on Sglt2 inhibitors?

 

[Cragwood]

I realise this is an old thread but I'm one of the 118 yellow card warnings that occurred in the UK - and I was one of the first 20 to be reported. I was newly diagnosed Type 2 and as I was having horrible side effects with Metformin, I was given Forxiga. I took it for about 3 weeks. My bg levels were fantastic. After about 2.5 weeks I started to feel like I had the worst case of 'flu ever! My husband took me to A&E because I was finding it difficult to even walk to the door. I saw an emergency doctor who was worried but as my BG levels were ok, wasn't sure what was going on. She was so worried that she insisted the ward run blood tests. It's lucky she did as it turned out I was in an advanced state of ketoacidosis. I was told had I not been admitted to ICU that night, I wouldn't have been alive the following day. For reference, I was not on a low carb diet or anything like that. Thankfully I made a full recovery but the damage had been done and I'm now insulin dependent. There is no way I would recommend this drug to anybody. I don't believe full testing has been done. The danger with this drug is that your bg levels may be exceptionally good but the damage is happening behind the scenes and if a doctor isn't on the ball, it can well be missed.

I was one of the yellow card warnings too. In fact I think your story in here saved my life. I was admitted through A&E with severe DKA within only a few days of being on Forxiga. Because my BG levels were low they didn’t know what was wrong until I showed them your warning in this forum. I was very ill and was in hospital for a week. I’m now also on insulin as a result of the damage caused.

 

[Bluetit1802]

I was one of the yellow card warnings too. In fact I think your story in here saved my life. I was admitted through A&E with severe DKA within only a few days of being on Forxiga. Because my BG levels were low they didn’t know what was wrong until I showed them your warning in this forum. I was very ill and was in hospital for a week. I’m now also on insulin as a result of the damage caused.

Blimey, what enormous luck you read that post.

 

[Brunneria]

I was one of the yellow card warnings too. In fact I think your story in here saved my life. I was admitted through A&E with severe DKA within only a few days of being on Forxiga. Because my BG levels were low they didn’t know what was wrong until I showed them your warning in this forum. I was very ill and was in hospital for a week. I’m now also on insulin as a result of the damage caused.

Thank heavens you are still with us.
And well done for pressing your case.

- and a huge thank you for coming back and telling us about it.

 

[Indy51]

Yet another scary (to say the least!) side effect:

https://www.bloombergquint.com/busi...-tied-to-rare-diabetes-drug-effect#gs.LMq10Tk