How SGLT2 inhibitors promote ketones

[Sugarstre]

Traditionally, ketones are thought to be created in any quantity from only 2 conditions.

1. Lack of glucose.
2. Lack of insulin.

SGLT2 inhibitors seem to have a third mechanism that promotes ketone formation even when more than adequate levels of blood glucose and insulin exist. (I'm not talking about how they can create Euglycemic DKA because of a masked insulin deficiency.)

Does anyone have a link to a research paper or article explaining a proposed mechanism for enhanced ketone production by SGLT2 inhibitor treatment in the presence of adequate insulin and glucose?

 

[EllieM]

Euglycemic Diabetic Ketoacidosis Caused by SGLT2 Inhibitors and a Ketogenic Diet: A Case Series and Review of Literature

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively novel class of oral medications for the treatment of type 2 diabetes mellitus (T2DM…

www.sciencedirect.com

is quite interesting

SGLT2 inhibitors inhibit glucose reabsorption by proximal renal tubules and lead to a switch from glucose to lipid utilization, thereby increasing production of ketones in the liver by increasing glucagon and decreasing the insulin-glucagon ratio. This leads to ketogenesis, gluconeogenesis, and glycogenolysis.1,13 SGLT2 inhibitors may cause glucagon secretion by a direct effect on pancreatic α-cells and also reduce renal ketone body clearance.13,14

Not sure whether this is what you are after (it's mostly about euDKA).

 

[Sugarstre]

Thanks. Yes it is interesting. A few mechanisms there besides simply reducing glucose.

Direct glucagon secretion and reduced ketone clearance,

Am having some elevated ketones now and may have to give up the Farxiga. Not looking forward to that as it just means MORE insulin and MORE weight gain.

Glucagon secretion would actually act to raise blood sugar wouldn't it?

 

[Oldvatr]

Traditionally, ketones are thought to be created in any quantity from only 2 conditions.

1. Lack of glucose.
2. Lack of insulin.

SGLT2 inhibitors seem to have a third mechanism that promotes ketone formation even when more than adequate levels of blood glucose and insulin exist. (I'm not talking about how they can create Euglycemic DKA because of a masked insulin deficiency.)

Does anyone have a link to a research paper or article explaining a proposed mechanism for enhanced ketone production by SGLT2 inhibitor treatment in the presence of adequate insulin and glucose?

View of SGLT2 inhibition and ketoacidosis – should we be concerned? | British Journal of Diabetes

www.bjd-abcd.com

 

[Oldvatr]

Thanks. Yes it is interesting. A few mechanisms there besides simply reducing glucose.

Direct glucagon secretion and reduced ketone clearance,

Am having some elevated ketones now and may have to give up the Farxiga. Not looking forward to that as it just means MORE insulin and MORE weight gain.

Glucagon secretion would actually act to raise blood sugar wouldn't it?

I too am trying to come off my Dapagliflozin. I had an episode where my ketones were running at 4mmol/l and then jumped to 8 mmol/l after a meal so not dietary ketosis. My GP refuses to take me off it, and is telling me he will stop my other diabetes meds if I stop it without permission. This is within the Nice guidelines since I am at prediabetic hba1c so technically non diabetic.

These meds are being offered as a miracle drug to treat many diseases, heart failure, CVD Parkninsons et al so I am immediately suspicious of any coecion to continue taking a med that in my case is causing significant discomfort. You may find it is not so easy to come off this med.

 

[Sugarstre]

I too am trying to come off my Dapagliflozin. I had an episode where my ketones were running at 4mmol/l and then jumped to 8 mmol/l after a meal so not dietary ketosis. My GP refuses to take me off it, and is telling me he will stop my other diabetes meds if I stop it without permission. This is within the Nice guidelines since I am at prediabetic hba1c so technically non diabetic.

These meds are being offered as a miracle drug to treat many diseases, heart failure, CVD Parkninsons et al so I am immediately suspicious of any coecion to continue taking a med that in my case is causing significant discomfort. You may find it is not so easy to come off this med.

I am quite diabetic, and I think there would be ethics violations if it was threatened to withhold my insulin. In my case, I would LIKE to take the drug, but am worried about a similar runaway ketones case. I am peaking daily around 2.0mmol/L.

For all its detractors and woes, this might be one of those case where the US health care system is better.

Should a doc ever threaten that here, you get an appointment with a new doc next week. I hope your situation resolves quickly.

 

[Oldvatr]

I pointed out to my GP that I have the option of diet control by ketosis. At the moment I eat a varied omnivore diet including bread and potatoes, but for keto I will probably go carni. He said the choice is mine to make.

I do not need to change GP since I have discovered that he is dancing to a higher authority's tune. and the dictat comes via the CCG from on high. someone up there has decided taking SGLT2 for everything is a good idea. Its a Wunderkindt, a miracle. Some cynics might say its a scam and a lot of money is tied up with promoting it. I reply that just reading the study reports, especially the Conflict of Interest sections, is enlightening, and I need not say more.

 

[Oldvatr]

If you follow a ketogenic diet, you can come out of ketosis quickly by eating a carby meal. With medication it is like jamming a spanner in the works, and it overrides the body's natural feedback control mechanisms. So your chemical induced ketosis will last the half life of the meds, which may be hours, or days before you can regain control. The euDKA if it occurs is difficult to regain control since it is no longer responsive to diet. when my ketones were 8 mmol.l then my bgl was only 6.2 mmol/l way below even euDKA caused by other diabetic meds. I did not get euDKA since I am on weak dose and the halflife is around 4 to 6 hours so it passed quickly. Note while in lipolysis, then the liver stops unloading glycogen for glucose so does not dump to compensate. As the med levels fall, then the liver starts to regain control and normality returns. Most people will not be aware of this unless they measure ketones, so will be unaware of how close to an acid buildup they are while taking this med. People with low eGFR or failing kidneys are more susceptible to buildup, so at increased risk. The prescribing info does not address this class of patient. But SGLT2 is now being given to cure kidney failure patients.

SGLT2 inhibitors

SGLT2 inhibitors are medicines that can help improve kidney and heart health for people living with CKD. They can also help people with type 2 diabetes manage their blood sugar.

www.kidney.org

However the FDA says it is contraindicated for eGFR below 45

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/202293s018lbl.pdf

Note Farxiga is known in the UK as Forziga
So people are being encouraged to use this Off Label.

 

[Sugarstre]

It has actually been a good drug for me for about 5 years. The long acting insulin I am on, cannot react to mealtime and so this drug helped shave off the spikes. It also allowed for lower doses of insulin, a med which for me packs on the pounds.

Nonetheless, even though my ketones are not DKA high, the recent increases make me feel like I am walking a tightrope..

 

[Oldvatr]

It has actually been a good drug for me for about 5 years. The long acting insulin I am on, cannot react to mealtime and so this drug helped shave off the spikes. It also allowed for lower doses of insulin, a med which for me packs on the pounds.

Nonetheless, even though my ketones are not DKA high, the recent increases make me feel like I am walking a tightrope..

It relies on the liver being able to pick up and take over as the drugs effects fade. As a T2D you have some function there, so while that continues you should avoid the problems. But I have seen papers that suggest you should not take the drug when your sugars are below a certain level (from memory about 110 mg/dl) to prevent acidosis. This is why T1D should not use this drug (but it is being offered off label to T1D which is not in the FDA licence. such users may be at risk as may be T2D with insufficiency.) As an orals only T2D I too feel I am walking a tighrope since I am not tested for liver sufficiency, and I am ignorant of my pancreas capability, and my recent ketone rise would indicate I too have conditions where I am at risk of euDKA. My GP has prescribed some new Ketostix to test my excretion.

I see the FDA are now reporting incidences of pancreatic cancer and precancer growths associated with these meds, along with the pancreatitis already on the label. The FDA has put these meds onto special watch from their yellow card reporting system.

 

[Sugarstre]

It relies on the liver being able to pick up and take over as the drugs effects fade. As a T2D you have some function there, so while that continues you should avoid the problems. But I have seen papers that suggest you should not take the drug when your sugars are below a certain level (from memory about 110 mg/dl) to prevent acidosis. This is why T1D should not use this drug (but it is being offered off label to T1D which is not in the FDA licence. such users may be at risk as may be T2D with insufficiency.) As an orals only T2D I too feel I am walking a tighrope since I am not tested for liver sufficiency, and I am ignorant of my pancreas capability, and my recent ketone rise would indicate I too have conditions where I am at risk of euDKA. My GP has prescribed some new Ketostix to test my excretion.

I see the FDA are now reporting incidences of pancreatic cancer and precancer growths associated with these meds, along with the pancreatitis already on the label. The FDA has put these meds onto special watch from their yellow card reporting system.

The reason for asking in this thread is, the drugs seems to be able to elevate ketones WITHOUT having low blood sugars.

The proposed mechanisms above are direct glucagon release from the liver and a reduction of ketone clearance in the kidneys. These mechanisms can work regardless of blood glucose levels.

 

[Oldvatr]

I am referrring back to some research papers on SGLT2 and euDKA. They suggest that low initial glucose levels may exacerbate the risk presented by lowered insulin levels. The body will synthesise glucose through gluconeogenesis to provide what the brain and nerves require, As you say it should not depend on diet or glucose levels, but even the .Gov advice cites low food intake as a factor.

SGLT2 inhibitors: updated advice on the risk of diabetic ketoacidosis

Test for raised ketones in patients with ketoacidosis symptoms, even if plasma glucose levels are near-normal.

www.gov.uk

Note too that a sudden drop in insulin dose can trigger DKA too it seems.

However, it seems that euDKA does not resolve in any particular group or setting

SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System - PubMed

A list of FDA reports analysed in the study is available in the figshare repository, 10.6084/m9.figshare.4903211 . Other data are available from the corresponding author on reasonable request.

pubmed.ncbi.nlm.nih.gov

It is also not dose dependant or duration of use dependant and some of the reported DKA on this forum have been newly prescribed.

 

[saky]

It relies on the liver being able to pick up and take over as the drugs effects fade. As a T2D you have some function there, so while that continues you should avoid the problems. But I have seen papers that suggest you should not take the drug when your sugars are below a certain level (from memory about 110 mg/dl) to prevent acidosis. This is why T1D should not use this drug (but it is being offered off label to T1D which is not in the FDA licence. such users may be at risk as may be T2D with insufficiency.) As an orals only T2D I too feel I am walking a tighrope since I am not tested for liver sufficiency, and I am ignorant of my pancreas capability, and my recent ketone rise would indicate I too have conditions where I am at risk of euDKA. My GP has prescribed some new Ketostix to test my excretion.

I see the FDA are now reporting incidences of pancreatic cancer and precancer growths associated with these meds, along with the pancreatitis already on the label. The FDA has put these meds onto special watch from their yellow card reporting system.

My mom had been taking linagliptin(trajenta) for more than a decade. Her kidneys began to fail(due to uncontrolled diabetes) and she got admitted in hospital due to worsening kidney condition where the doctors found pancreatitis also- high levels of amylase and lipase. Taken off linagliptin and using insulin now. Am sure linagliptin caused pancreatitis (vomitting etc when she takes trajenta, unable to eat etc). Now she doesn't vomit after eating.

 

[Sugarstre]

I am referrring back to some research papers on SGLT2 and euDKA. They suggest that low initial glucose levels may exacerbate the risk presented by lowered insulin levels. The body will synthesise glucose through gluconeogenesis to provide what the brain and nerves require, As you say it should not depend on diet or glucose levels, but even the .Gov advice cites low food intake as a factor.

SGLT2 inhibitors: updated advice on the risk of diabetic ketoacidosis

Test for raised ketones in patients with ketoacidosis symptoms, even if plasma glucose levels are near-normal.

www.gov.uk

Note too that a sudden drop in insulin dose can trigger DKA too it seems.

However, it seems that euDKA does not resolve in any particular group or setting

SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System - PubMed

A list of FDA reports analysed in the study is available in the figshare repository, 10.6084/m9.figshare.4903211 . Other data are available from the corresponding author on reasonable request.

pubmed.ncbi.nlm.nih.gov

It is also not dose dependant or duration of use dependant and some of the reported DKA on this forum have been newly prescribed.

It makes sense that ketone formation would be higher with low glucose or low insulin levels. These are the classical cases of ketone formation.

It's interesting to me that these drugs seem to promote ketone formation regardless of glucose or insulin levels.

 

[Oldvatr]

It makes sense that ketone formation would be higher with low glucose or low insulin levels. These are the classical cases of ketone formation.

It's interesting to me that these drugs seem to promote ketone formation regardless of glucose or insulin levels.

As I said- spanner in the works jobbie. It actually lowers insulin levels from the pancreas by boosting glucagon so overrides the normal control mechanisms. ( so sugar levels dropping would normally slowly turn off insulin to prevent hypo. This drug forces lipolysis (ie ketosis) instead so glucose does not drop due to insulin, but by excretion.) The drug not only stops glucose being recycled via the kidneys, it interferes with the filtering out of ketones epecially the butyrate one hence the buildup in the blood. It is strongly contraindicated in patients who have renal impairement.

Not sure what the effect is for exogenous insulin users. It seeems to be safe, but the drug itself is only approved and validated for T2D non insulin users. It seems that SGLT2 may require reduction of insulin dose. There does seem to be an associaton of an increased risk of DKA in T2D insulin users. There is an association of increased incidence of GTI in insulin users with this med.

 

[Sugarstre]

As I said- spanner in the works jobbie. It actually lowers insulin levels from the pancreas by boosting glucagon so overrides the normal control mechanisms. ( so sugar levels dropping would normally slowly turn off insulin to prevent hypo. This drug forces lipolysis (ie ketosis) instead so glucose does not drop due to insulin, but by excretion.) The drug not only stops glucose being recycled via the kidneys, it interferes with the filtering out of ketones epecially the butyrate one hence the buildup in the blood. It is strongly contraindicated in patients who have renal impairement.

Not sure what the effect is for exogenous insulin users. It seeems to be safe, but the drug itself is only approved and validated for T2D non insulin users. It seems that SGLT2 may require reduction of insulin dose. There does seem to be an associaton of an increased risk of DKA in T2D insulin users. There is an association of increased incidence of GTI in insulin users with this med.

Maybe a change in terminology from over the pond. Many T2D users here (US) use exogenous insulin and Farxiga is approved in this setting.

In my case, I am an exogenous insulin user and see a rise in ketones with this drug, so perhaps not perfectly safe for us either. So far my ketone levels have remained below 2 and I hope they stay that way.

My first case of elevated ketones occurred prior to starting insulin therapy. We discontinued Farxiga and started long acting insulin. After quickly increasing doses of insulin, it was thought to restart Farxiga as now there presumably would be adequate insulin coverage to prevent ketone formation. Ketones did stay low for about 2 years, bit now despite a very high insulin dose they still are forming.

 

[Oldvatr]

Maybe a change in terminology from over the pond. Many T2D users here (US) use exogenous insulin and Farxiga is approved in this setting.

In my case, I am an exogenous insulin user and see a rise in ketones with this drug, so perhaps not perfectly safe for us either. So far my ketone levels have remained below 2 and I hope they stay that way.

My first case of elevated ketones occurred prior to starting insulin therapy. We discontinued Farxiga and started long acting insulin. After quickly increasing doses of insulin, it was thought to restart Farxiga as now there presumably would be adequate insulin coverage to prevent ketone formation. Ketones did stay low for about 2 years, bit now despite a very high insulin dose they still are forming.

indeed it is approved for T2D but contra indicated in T1D. The FDA approval says use with caution for combined use with insulin for T2D so it is not a blanket clearance. The problem seems to be related to the lower blood sugars leading to a reduction of insulin which for T1D is a suspected trigger for euDKA. Not sure why the same is not relevant to ID T2D. Remember that the SGLT2 reduces endogenous insulin as part of its action. but presumably there will be residual output to prevent DKA. Does that cover cases of severe Insulin deficiency?

Sodium-glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: Clinical perspectives - PMC

The treatment of type 2 diabetes is a challenging problem. Most subjects with type 2 diabetes have progression of beta cell failure necessitating the addition of multiple antidiabetic agents and eventually use of insulin. Intensification of insulin ...

www.ncbi.nlm.nih.gov

One thing I learnt from my research and which is unconnected to ID or not ID is that SGLT2 meds reduce creatinine clearance in the urine. So it builds up in the plasma instead. This explains why my eGFR has dropped considerably, and my plasma creatinine levels have risen way above normal. My GP says it is because I am eating too much animal based product and fat and that my kidneys are failing. But I must stay on my SGLT2 since it apparently improves renal function (something amiss here)

 

[Sugarstre]

indeed it is approved for T2D but contra indicated in T1D. The FDA approval says use with caution for combined use with insulin for T2D so it is not a blanket clearance. The problem seems to be related to the lower blood sugars leading to a reduction of insulin which for T1D is a suspected trigger for euDKA. Not sure why the same is not relevant to ID T2D. Remember that the SGLT2 reduces endogenous insulin as part of its action. but presumably there will be residual output to prevent DKA. Does that cover cases of severe Insulin deficiency?

Sodium-glucose cotransporter 2 inhibitors with insulin in type 2 diabetes: Clinical perspectives - PMC

The treatment of type 2 diabetes is a challenging problem. Most subjects with type 2 diabetes have progression of beta cell failure necessitating the addition of multiple antidiabetic agents and eventually use of insulin. Intensification of insulin ...

www.ncbi.nlm.nih.gov

One thing I learnt from my research and which is unconnected to ID or not ID is that SGLT2 meds reduce creatinine clearance in the urine. So it builds up in the plasma instead. This explains why my eGFR has dropped considerably, and my plasma creatinine levels have risen way above normal. My GP says it is because I am eating too much animal based product and fat and that my kidneys are failing. But I must stay on my SGLT2 since it apparently improves renal function (something amiss here)

As SGLT2i reduce endogenous insulin, using with exogenous insulin actually reduces the risks of DKA.

I also do not understand the new indication of SGLT2i for kidney disease, when that is a contraindication for SGLT2i.

 

[Oldvatr]

As SGLT2i reduce endogenous insulin, using with exogenous insulin actually reduces the risks of DKA.

I also do not understand the new indication of SGLT2i for kidney disease, when that is a contraindication for SGLT2i.

You would think it should be the other way around, but the preponderance of euDKA occurs in insulin users.

SLGT2 meds are generally considered a miracle drug for reducing kidney disease in people with eGFR > 60, but is strongly contraindicated for those with eGFR < 45. As noted, this med reduces eGFR artificially by reducing excretion of creatinine. Note to self - stop taking it at least 2 days before blood panel draw.

 

[Sugarstre]

You would think it should be the other way around, but the preponderance of euDKA occurs in insulin users.

SLGT2 meds are generally considered a miracle drug for reducing kidney disease in people with eGFR > 60, but is strongly contraindicated for those with eGFR < 45. As noted, this med reduces eGFR artificially by reducing excretion of creatinine. Note to self - stop taking it at least 2 days before blood panel draw.

Yes, because the preponderance of euDKA events occur in Type 1 diabetics.

In T2D, exogenous insulin is protective, yet not absolutely, of DKA.