Surrey (East Surrey CCG, Guildford & Waverley CCG, North West
Surrey CCG, Surrey Downs CCG & Surrey Heath) North East
Hampshire & Farnham CCG, Crawley CCG and Horsham & MidSussex CCG
Metformin: change of licence in renal failure
For consideration by the PCN June 2015
The Issue:
Recently Glucophage SR changed its SPC to state that:
A contraindication for use of Glucophage SR is in patient with renal failure or renal
dysfunction (creatinine clearance < 60 ml/min).
The same is now true for all metfomin SPCs.
The BNF still has the advice:
Use with caution in renal impairment—increased risk of lactic acidosis; avoid in significant
renal impairment. NICE(1) recommends that the dose should be reviewed if eGFR less than
45 mL/minute/1.73 m2 and to avoid if eGFR less than 30 mL/minute/1.73 m2. Withdraw or
interrupt treatment in those at risk of tissue hypoxia or sudden deterioration in renal function,
such as those with dehydration, severe infection, shock, sepsis, acute heart failure,
respiratory failure or hepatic impairment, or those who have recently had a myocardial
infarction
Following the SPC guidance could mean that many patients with diabetes would have to go
onto other therapies which may not be as effective and do not have the positive CVD
outcomes that metformin does. Current practice in relation to the use of metformin in renal
impairment is as advised in the BNF.
Advice received from renal specialists:
Advice has been sought of the local renal clinicians in Surrey in relation to this matter and
the responses received are as follows:
I am happy that you stick to the present advice.
I think this is overly cautious and not supported by any worthwhile evidence base. However,
in the days of defensive medicine, I understand why you may take this view.
Manufacturers of more expensive alternatives will certainly be supportive.
The real shame is that some patients will be transferred to insulin when this will absolutely
NOT be in their best interests.
I have a similar practice to my colleagues. Happy to prescribe to eGFR 20 -25, especially in
stable patients.
Perminder Oberai, NW Surrey CCG, May 2015
There is increasing talk in the literature on both sides of the debate - the short answer is that
it is likely safe with eGFR 30-60 but the product literature is not supporting this
I think that Metformin is perhaps underprescribed in the fear of lactic acidosis. In the majority
of cases, I would carry on with Metformin as long as the GFR is above 30. In my overweight
and very stable CKD patients, I would continue to prescribe Metformin (at reduced doses)
even when the GFR falls below 30. I warn however my patients to stop it (along with ACEi
and ARB) in the event of an acute illness and/or dehydration. I would definitively stop
Metformin when the GFR is down to 25 or below.
A few of the renal consultants are soon going to present their findings of a review of
metformin use in CKD.
One recent Study re metformin and CKD:
Metformin in Patients With Type 2 Diabetes and Kidney Disease
Inzucchi
SE,
Lipska
KJ,
Mayo
H,
Bailey
CJ,
McGuire
DK
JAMA. 2014;312:2668-2675
Background: Metformin and Chronic Kidney Disease
Diabetes mellitus is the leading cause of chronic kidney disease (CKD) in the United States.
For decades, a mainstay of therapy against diabetes has been metformin. Metformin has the
advantage of being an effective antihyperglycemic agent that also facilitates weight loss;
however, it is considered unsafe in patients with renal insufficiency because of fears about
lactic acid accumulation. Thus, since its approval by the US Food and Drug Administration in
1994, healthcare providers have been cautioned against the use of metformin in patients
with CKD, a measure that has prevented these patients from availing themselves of the
beneficial effects of metformin.
Fears about metformin use in patients with CKD stem from the theoretical ability of the drug
to generate large amounts of lactic acid. Metformin inhibits the respiratory chain within the
mitochondria, forcing cells in the body to perform anaerobic metabolism (metabolism that
does not use oxygen). A large by-product of anaerobic metabolism is lactic acid, which
acidifies the blood and, if present in a high concentration, can cause multiorgan dysfunction.
Because the kidneys excrete metformin, any degree of kidney dysfunction would increase
the level of metformin and the subsequent lactic acid produced. Now, a large systematic
review calls into question whether this theoretical concern is supported by empirical realworld data.
The Study
Inzucchi and colleagues analyzed results of clinical and observational studies to suggest that
reservations about using metformin in patients with CKD are not borne out in the data.
Empirical data[1] have indeed shown a reduction in metformin clearance as kidney
dysfunction worsens (a 23%-33% reduction when the creatinine clearance is 60-90 mL/min,
and a 74%-78% reduction when the creatinine clearance is 30-60 mL/min). Of interest, in
that study, metformin levels were maintained within the therapeutic range (4-20 μmol/L)
regardless of the creatinine clearance, suggesting that despite a reduction in drug clearance,
there is no increase in metformin toxicity.
In another independent study,[2] the observed metformin levels at various stages of CKD
were measured, and all were within the drug's broad therapeutic range (4.5 μmol/L for an
estimated glomerular filtration rate [eGFR] > 60 mL/min/1.73 m2; 7.71 μmol/L for an eGFR of
30-60 mL/min/1.73 m2; and 8.88 μmol/L for an eGFR< 30 mL/min/1.73 m2).
Unfortunately, the authors of the current study were unable to find equally robust data
regarding the levels of lactic acid generated in patients with various degrees of kidney
function who were taking metformin. Many of the studies that focused on lactic acid
production excluded patients with CKD; other studies did not perform propensity-score
Perminder Oberai, NW Surrey CCG, May 2015
adjustments to account for confounding. The available data suggest that the degree of lactic
acidosis seen in diabetic patients taking metformin is similar to that in patients taking other
antidiabetic medications (eg, sulfonylureas) or in those taking no medications at all.
Commentary
Despite these shortcomings, this systematic review revisits the notion that metformin is
unequivocally unsafe in patients with CKD. Given its low cost, proven effectiveness against
hyperglycemia, and positive secondary effects (eg, weight loss), metformin is an attractive
drug for many patients with diabetes, including those with kidney disease. The authors
recognize the value of using metformin in patients with CKD and offer an alternative dosing
strategy that opens its use to more patients, with doses ranging from 2550 mg for patients
with an eGFR ≥ 90 mL/min/1.73 m2 down to 1000 mg for those with an eGFR of 30 to < 45
mL/min/1.73 m2, and recommendations to avoid use in those with an eGFR below 30
mL/min/1.73 m2.
Compiling all of the available data into a systematic review offers a concise perspective on
the question of the safety of metformin in patients with CKD. Although some providers may
continue to wonder whether long-term metformin use could lead to the deleterious effects
initially feared, this review opens the possibility of welcoming back metformin into the family
of antihyperglycemic drugs that many kidney disease patients need.
Decision required re advice to primary care clinicians:
-
Continue with advice in line with the current recommendation in the BNF / NICE CG
87 (May 2009): Type 2 diabetes: The management of type 2 diabetes / local renal
clinicians
-
Advice given in line with the SPCs
Note: NICE have been contacted in relation to this matter
Perminder Oberai, NW Surrey CCG, May 2015