Metformin and kidney function

[LittleGreyCat]

I am currently on 3 * 500 mg - two in the morning and one in the evening.

My latest HbA1c was 47/6.4 which is just inside pre-diabetic (just below diabetic). This has been pretty consistent although I know I could do better.

My eGFR was down to 58 mL/min which is a sign of kidneys not doing their job properly. Although eating a lot of protein and not drinking a lot of water and exercising quite a bit can all skew the figures.

Anyway, my DSN advised dropping to 2 * 500 mg Metformin because my HbA1c was consistently in a good range (from her point of view) and it was more important to address the possible kidney issues.

Noting that my eGFR has been that low before and has also been up in the '80s so go figure.

Anyway, happy to drop the Metformin dosage but wondering if I should go the whole hog and come off Metformin completely for a little (in a phased manner). Metformin has many good aspects, but dodgy kidneys might be more of an issue than a slightly dodgy pancreas and harder to fix.

Has anyone else had similar issues with kidney function and Metformin?

 

[Struma]

The recommendations for metformin and kidney function have been revised recently.

NiCE - review metformin when eGFR 45 (used to be review if <60,) stop if <30.

https://www.nice.org.uk/guidance/ng28/chapter/1-recommendations (at the bottom.)

 

[PatsyB]

Just received a text from my Doctors asking me to make a non fasting blood test appointment for kidney function and to take a sample in so will call in this morning and book that am interested to know what the results are as take 2 x 500 in the morning and 2 x 500 at tea time.

 

[LittleGreyCat]

Well, I took the plunge and scaled down quite rapidly to being Metformin free.

I don't feel any different, apart from wondering if my taste buds have perked up a bit.
However I have had a more severe attack of the munchies than usual.
I also seem to put on a couple of pounds at the drop of a hat.
So that fits with the long list of side effects.

BG testing shows that I am running higher BG levels and I don't seem to be able to get away with the occasional lapses any more without going into the 9s.

I'm being quite strict on my diet at the moment and testing more so I don't have an accurate baseline to compare against.
A proper scientist would have tested for a week or so before coming off the pills!

Anyway, my HbA1c of 6.4 reflects an average BG of 7.6 which is not that far off some of my readings, but certainly lower.

If my average has gone up one whole point to 8.6 that would give an HbA1c of 7 which is well into the diabetic range (although I have seen worse in the past).

Anyway, I think that this justifies running a little longer without Metformin, and perhaps ordering a home HbA1c test kit just to check that I don't have hidden highs taking me further into the danger zone.

Nobody so far (and there is another recent question posted by @Fraser5 ) has cleared up WHY they review Metformin and recommend ceasing at certain eGFR levels. The implication is that Metformin has an impact on kidney function, but I would have expected that with so many long term users of Metformin somebody on this Forum would already have hit the issue.

Edit:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797060/

This study shows some impact on eGFR when comparing people who stayed on Metformin and those who came off for 100 days. The up front concern seems to be the risk of slow clearance of Metformin from the blood stream and the risk of lactic acidosis.

Need more time to read the full article. It may suggest why eGFR is impacted.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427053/ focuses on the risk of Lactic Acidosis and (I think) concludes that there is little extra risk as long as your eGFR is 30 or above.

More later.
For I have promises to keep, and miles to go before I sleep.

 

[LittleGreyCat]

Further information on the first study:
[Note: I think the first study references the second study.]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797060/

"The patients in the metformin interruption group were younger, had a higher level of glycated hemoglobin (HbA1c), increased use of anti-diabetic drugs including α-glucosidase inhibitors, dipeptidyl peptidase-4 (DDP-4) inhibitors and insulin, and increased use of statins compared to those in the metformin continuation group"

So a level playing field then. Statistics speaker needed to decide if the differences are significant.

My statistical knowledge isn't good enough to interpret all the probabilities, perhaps someone else can comment?

It does, however, say:

"In this retrospective cohort study, the patients with type 2 DM who received metformin therapy for at least 6 months had a greater decline in eGFR if they continued metformin therapy compared to those who discontinued metformin treatment for at least 100 days. The continuation of metformin therapy was significantly associated with a decline in renal function in the patients with DM and moderate CKD. Other risk factors for a decline in renal function included high serum LDL-C, high HbA1c, low baseline eGFR, high uric acid level, high UACR, and the use of ACEIs and/or ARBs."

From the pretty pictures it looks as though eGFR improved in those off Metformin for 100 days, but got worse in the ones still on Metformin. The implication from this is that Metformin is associated a deleterious effect on eGFR but the patients in the trial were on such a cocktail of drugs that I'm not sure how this relates to someone with reasonable control and just Metformin.

Also:

"A previous clinical study demonstrated that metformin users with a renal function of eGFR <60 mL/min/1.73 m2 had a higher risk of lactic acidosis or elevated lactate concentrations [16]. Metformin-associated lactic acidosis can cause metabolic acidosis in patients with moderate CKD, and this has been shown to have a deleterious effect on renal function leading to a decline in eGFR and progression of CKD [17–19]. Several factors have been associated with the effect of metabolic acidosis on the decline in renal function, including ammonia-induced complement activation and acidosis-induced increased production of endothelin and aldosterone [19]. Taken together, all of these factors can cause tubule-interstitial injury and mediate a decline in eGFR [19], which may explain the inconsistent findings with regards to the effect of metformin on renal function."

So (I think) more lactate in the blood and more acid blood may explain the kidney damage.

"Diabetic nephropathy is associated with oxidative stress caused by a persistent hyperglycemic state and increase in advanced glycation end products [20]."

Which then raises the question "Is higher BG due to not taking Metformin more of a risk to the kidneys than a lower BG and taking Metformin?".

It does say:
"In conclusion, continuous metformin treatment in patients with DM and moderate CKD was associated with a worsening in renal function. Metformin is currently indicated for diabetic patients with eGFR > 30 ml/min/1.73 m2. However, according to the findings of the present study, metformin should be prescribed with caution for patients with DM and moderate CKD, and renal function should be followed closely in these patients."

O.K. - losing the will to live here.

I think I have seen that in the cohort of patients in the first study eGFR worsened over the trial period for those on Metformin and improved for those not on Metformin but the improvement was not as fast as the worsening. In other words you would have to spend more time off Metformin than on to maintain a steady eGFR (all other things being equal).

As I said above, it is not clear if the risks of running a higher BG are worse than using Metformin when you have moderate chronic CKD.

• Stage 3A Moderate CKD (GFR = 45-59 mL/min)
• Stage 3B Moderate CKD (GFR = 30-44 mL/min)

So not really that much wiser apart from there being at least one study where there has been a noted difference in the progress of CKD when using Metformin. Although I haven't managed to interpret how fast the deterioration is.

Bootnote: my eGFR has been up and down like a roller blind over the years and I have been on Metformin for a number of years, so this may not be the whole story.

 

[LittleGreyCat]

Just received a text from my Doctors asking me to make a non fasting blood test appointment for kidney function and to take a sample in so will call in this morning and book that am interested to know what the results are as take 2 x 500 in the morning and 2 x 500 at tea time.

And the results were....?

 

[PatsyB]

No idea no one has informed me so will have to wait until I go see the Nurse in December