Advances in Medical Sciences

Vol. 57(1) 2012 pp 65-70 DOI: 10.2478/v10039-012-0017-7

Medical University of Bialystok, Poland

Inappropriate metformin prescribing in elderly

type 2 diabetes mellitus (T2DM) patients
Kosmalski M, Drozdowska A, Sliwinska A, Drzewoski J*
Department of Internal Disease, Diabetology and Clinical Pharmacology, Medical University of Lodz, Zgierz, Poland

* CORRESPONDING AUTHOR:
Department of Internal Disease, Diabetology and Clinical Pharmacology,
Medical University of Lodz,
Parzeczewska 35,
95-100 Zgierz, Poland
Tel./Fax: +48 42 714 45 51,
e-mail: jdrzew@poczta.onet.pl (Jozef Drzewoski)

Received 13.12.2011
Accepted 07.03.2012
Advances in Medical Sciences
Vol. 57(1) 2012 pp 65-70
DOI: 10.2478/v10039-012-0017-7
Medical University of Bialystok, Poland

ABSTRACT
Purpose: Metformin is the most commonly prescribed anti-diabetic medication. However, it is often used despite the presence
of contraindications and in unlicensed indications. The main aim of this study was to evaluate the frequency of metformin
use before hospitalization in spite of contraindications in patients with type 2 diabetes mellitus (T2DM) and to evaluate the
prevalence of metformin - associated side effects.
Material/Methods: 558 hospitalized patients (mean age = 66.6512.73 years) with poorly controlled T2DM were enrolled.
Detailed medical history including the duration of T2DM, duration of hypoglycemic agents usage prior to hospitalization and
possible metforminassociated side effects was recorded. Patients were subjected to a thorough physical examination and
indispensable biochemical and diagnostic research panel was performed to establish the degree of heart failure, sufficiency of
the respiratory system and kidney function.
Results: 335 out of 558 patients were treated before hospitalization with metformin alone or in combination with other
hypoglycemic agents, mostly sulfonylureas. Contraindications to metformin were found in 275 patients and despite this 120
of them were using this medication in an average dose of 1793.91701.61 mg. However, none of them reported any serious
adverse effects and no significant pH changes were observed. Only three patients reported moderate dyspepsia.
Conclusions: The results of this study indicate a relatively good tolerability of metformin by patients with the traditional
contraindications to this drug. These findings support other authors suggestion that indications and contraindications to
metformin should be re-evaluated.
Key words: diabetes mellitus, metformin, off label use, prescription, side effects

INTRODUCTION
Metformin is an oral antihyperglycemic agent that has
been used in Europe for over 50 years for type 2 diabetes
(T2DM) treatment. Current American Diabetes Association
and European Association for the Study of Diabetes expert
consensus statement on the approach to the management of
hyperglycemia in individuals with T2DM underlines the role
of using metformin as a safe, effective antihyperglycemic agent
available in inexpensive generic form, together with lifestyle
changes at the time of diagnosis [1]. Therefore, metformin has
become the most frequently prescribed antidiabetic medication
in the world.

When used as labeled, metformin is effective and generally

well - tolerated with the most common adverse effects being
gastrointestinal. However, this old drug is often used off-label
to assist with weight loss, polycystic ovary syndrome, non
alcoholic fatty liver disease, gestational diabetes and HIV
lipodystrophy syndrome. Moreover, the drug is sometimes
prescribed to patients with absolute contraindications, including
kidney, cardiovascular, pulmonary and hepatic disease, and
advanced age. As a result of metformin use in non- approved
indications, the risk of serious side effects, especially lifethreatening lactic acidosis (LA), may substantially increase
[2].

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Inappropriate metformin prescribing in elderly type 2 diabetes mellitus (T2DM) patients

Table 1. Characteristics of the patients with contraindications to metformin who were (Group A) and who were not treated with the
drug (Group B).
Mean SD
Group A (n= 120)

Group B (n= 155)

Age (years)

68.77 11.80

73.00 12.40

P=0.004

Duration of diabetes (years)

7.48 4.82

7.65 6.12

P=0.803

Body mass (kg)

83.12 20.20

77.80 14.55

P=0.012
P=0.123

BMI (kg/m2)

30.48 5.95

29.47 4.87

Waist circumference (cm)

106.27 14.26

103.55 10.92

P=0.074

Hip circumference (cm)

111.40 14.72

108.36 10.71

P=0.049

WHR

0.95 0.07

0.95 0.07

P=1

Systolic blood pressure (mmHg)

139.44 30.56

133.60 24.14

P=0.078
P=0.033

Diastolic blood pressure (mmHg)

78.56 15.01

75.18 11.14

Creatinine (mmol/l)

105.82 59.14

112.98 66.79

P=0.355

Urea (mmol/l)

9.13 5.91

9.98 6.79

P=0.277

GFR (ml/min/1.73m2)

69.09 34.68

67.77 42.49

P=0.782

Fasting glycemia (mmol/l)

9.92 4.04

8.66 4.14

P=0.012

Postprandial glycemia (mmol/l)

12.82 6.79

12.55 6.64

P=0.741

A1C (%)

9.12 2.08

8.56 1.94

P=0.022

354.37 121.79

P=0.443

Urea acid (umol/l)

365.70 120.73

TCH (mmol/l)

4.31 1.25

4.16 1.20

P=0.314

LDL-CH (mmol/l)

2.52 1.15

2.38 1.07

P=0.299

HDL-CH (mmol/l)

1.02 0.43

1.05 0.40

P=0.551

TG (mmol/l)

1.85 1.44

1.74 1.45

P=0.532

Total bilirubine (umol/l)

13.08 8.04

14.43 23.50

P=0.547

ALT (U/l)

44.75 59.54

28.31 28.51

P=0.003

ASP (U/l)

45.46 62.79

32.71 51.02

P=0.067

GGT (U/l)

80.77 116.88

86.97 233.96

P=0.791

A1C - glycated hemoglobin , ALT - alanine aminotransferase, ASP - aspartate aminotransferase, BMI - body mass index, GFR - glomerular
filtration rate, GGT - gamma-glutamyl transferase, HDL-CH - HDL cholesterol, LDL-CH - LDL cholesterol, TCH- Total cholesterol,
TG - triglycerides, WHR - waist to hip ratio.

Given that little information is available on inappropriate

metformin prescribing for elderly T2DM patients in Poland,
we examined the frequency of metformin administration and
occurrence of adverse side effects associated with inappropriate
use of this agent among patients admitted to hospital for poor
metabolic control and coexisting comorbidities.

MATERIAL AND METHODS

The study involved 558 consecutive T2DM patients (mean
age = 66.65 12.73 years) diagnosed and treated by general
practitioners (GPs) or diabetologists, hospitalized in the
Department of Internal Diseases, Diabetology and Clinical
Pharmacology of the Medical University of Lodz from 2009 to
2011 for management of uncontrolled hyperglycemia, diabetes
complications and/or associated comorbidities.
On admission we obtained information concerning current
symptoms, duration of diabetes, history of hyperglycemia
treatment, the dose of metformin taken before hospitalization

and the duration of exposure to this agent, presence or absence

of chronic renal, liver, lungs, and cardiovascular diseases,
and the history of alcohol overuse from the patients using a
combination of patient-self report or family members report,
physical examination, and a review of clinical records.
Congestive heart failure (CHF) was recognized in the
presence of symptoms reported by the patient making it possible
to identify a III or IV class according to the classification of
the New York Heart Association (NYHA). This diagnosis was
verified by additional physical examination and laboratory
or imaging test according to the guidelines proposed by the
European Society of Cardiology (ESC) in 2008.
Chronic renal dysfunction was defined as a GFR <60 ml/
min/1.73m2 for 3 months, with or without kidney damage.
Liver dysfunction was defined as a elevation of the liver
enzymes activity (alanine aminotransferase (ALT), aspartate
aminotransferase (ASP)) >3- fold above normal range and
the presence of common symptoms of liver dysfunction.
Patients were considered to have chronic respiratory failure
if the diagnosis was made before hospitalization and if they

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Kosmalski M et al.

Table 2. Prevalance of contraindications to metformin in patients who were (Group A) and who were not treated with the drug
(Group B).
Variables

Group A (n= 120)

Group B (n=155)

P value

Congestive heart failure

69

108

P=0.037

Chronic renal dysfunction

56

85

P=0.178

Liver dysfunction

20

P=0.003

Chronic respiratory failure

14

15

P=0.597

Alcohol dependency syndrome

10

P=0.192

Drug intolerance

P=0.514

were taking medication for the underlying cause of respiratory

dysfunction.
For each patient, blood pressure and the following
anthropometric indicators were measured: height, body mass,
waist and hip circumference (to calculate BMI and WHR
indexes). Fasting blood sample was taken for the following
analyses: glucose, glycated hemoglobin (A1C), urea,
creatinine, total bilirubin, uric acid, lipid profile and activity of
ALT, ASP and gamma-glutamyl transferase (GGT). Using the
Cocrofta-Gaults formula the glomerular filtration rate (GFR)
was calculated.
The patients with diagnosed contraindications to metformin
were assigned to two groups: patients who were treated with
metformin despite contraindications and patients who were
not treated with metfromin according to the current guideline.
Statistical analysis: Mean and standard deviations
were calculated for normally distributed data. Groups were
compared for significance by One-way ANOVA (Tab. 1). Chisquare tests (Tab. 2) were used to assess the distributions of
contraindications to metformin. A value of p<0.05 was taken
to indicate statistical significance. Analyses were performed
using STATISTICA 6.0 package (Statsoft, Tulsa, OK, USA).

RESULTS
Of the entire group of T2DM hospitalized patients enrolled
in this study, 335 were treated with metformin and 275 of
them (173 females and 102 men) had generally accepted
contraindications to this drug. 155 of 275 individuals (mean
age = 73.00 12.40 years) were non- metformin treated before
hospitalization and 120 (mean age = 68.77 11.80 years) were
receiving metformin at a daily average dose of 1793.91 701.61
mg. We were not able to collect the precise data regarding the
duration of metformin exposure before hospitalization from
majority of the patients, the main reason being the lack of
reliable data from the patients or their relatives.
Patients who were treated with metformin were younger,
had higher body mass and waist circumference and statistically
higher level of HbA1c than non-metformin users. Baseline
characteristics of metformin treated and non-metformin treated
patients are shown in Tab. 1.
Our results revealed that 69 out of 120 diabetes patients
were treated with metformin before hospitalizaton in spite of

congestive heart failure (II - IV class ac. NYHA). Chronic

renal dysfunction was diagnosed in 56 patients taking
metformin (GFR <60 ml/min). Twenty patients were treated
with this agent in spite of liver impairememet and 10 patients
were diagnosed with alcohol dependence syndrome. Chronic
pulmonary disease (chronic obstructive pulmonary disease,
asthma), accompanied by respiratory failure was diagnosed
in 14 patients. Distribution of contraindications in metformin
treated and non-treated patients is presented in Tab. 2.
We found that 75 patients had at least one contraindication
to metformin, 36 patients had two, and three had nine.
Surprisingly, none of the patients with contraindications to
metformin reported clinical symptoms that could suggest
lactic acidosis (LA) and only three metformin users reported
chronic dyspeptic symptoms, which had developed before
hospitalization. Lack of clinical symptoms suggesting lactic
acidosis and the fact that in all patients blood pH was at normal
range (7.35 7.45) we decided not to measure the level of
lactic acid in the blood.

DISCUSSION
To our best knowledge there is a lack of information on
unlicensed metformin use in Polish patients with T2DM.
Traditional contraindications to this agent include: renal
insufficiency, respiratory and heart failure, and liver
dysfunction. Our findings constitute the first evidence in the
Polish professional literature that a substantial proportion of
elderly type 2 diabetics are treated in out-patients setting with
metformin despite the presence of traditional contraindications.
It should be underlined that in some of them we identified
more than one contraindication. Interestingly, treatment with
a moderate dose of metformin (maximum recommended daily
dose of metformin for people over 17 years is 2550 mg) was
well tolerated by these patients. Moreover, none of the patients
complained of any significant adverse effects, including
symptoms suggesting LA.
Of note, several recent studies have suggested that despite
contraindications metformin was used by 24.5 to almost 85%
of examined patients with T2DM. In the majority of cases,
the drug had been previously prescribed by GPs. Chronic
renal failure proved to be the commonest contraindication,
followed by advanced cardiac insufficiency and age above 80

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Inappropriate metformin prescribing in elderly type 2 diabetes mellitus (T2DM) patients

years. Interestingly enough, no cases of LA were noticed and

metformin usage, even in the presence of contraindications,
did not affect the risk of hospitalization or death comparing
with non-users of this drug [3-6]. Although the incidence of LA
in metformin-treated patients is quite rare, this complication
involves very high mortality [7]. Of note, LA occurs also in
non-diabetic patients in case of severe infection, cancer, liver
and renal failure, with fatal outcome unless the underlying
condition is corrected. Therefore, pure type B LA (caused by
the accumulation of the drug) in metformin-treated patients,
without coexisting hypoxic factors is diagnosed extremely
rarely [8].
Several studies have shown that plasma metformin levels
were not correlated to blood lactate levels, which raises doubts
whether this drug is a causal factor in LA [7-9]. It should be
stressed that in our study in all patients with contraindications
to metformin no cases of significant pH blood changes were
noted. Similarly to other studies, among contraindications,
we found the prevalence of chronic renal insufficiency and
congestive heart failure, 56 and 46%, respectively.
The incidence of LA in metformin users, reported in
several studies, is equal or even lower in comparison with the
general population of T2DM patients. Of note, in the majority
of LA cases, especially fatal ones, the primary cause of this
life-threatening complication was the presence of underlying
conditions rather than metformin usage per se. Among
coexisting disorders influencing LA development, renal and
congestive heart failure were most often diagnosed [4,10-12].
It is well established that long lasting hyperglycemia in
patients with T2DM connected with accelerated coronary
atherosclerosis is associated with the higher cardiovascular
risk. Metformin, having insulin-sensitizing properties,
has a beneficial effect on cardiovascular risk factors but is
contraindicated in advanced or decompensated heart failure
[13].
Shah et al. [14], observing 401 patients with T2DM and
advanced systolic heart failure using metformin for 14 years
found that the treatment was safe and associated with better
survival. Independently of antihyperglycemic effect, metformin
was proved to improve the function of the myocardium via
activation of a signaling mechanism (AMP-activated protein
kinase), acting at the molecular level. Such a beneficial impact
of metformin may in the future contribute to the usage of this
drug in the treatment of heart failure, irrespective of coexisting
diabetes.
It is also well known that the positive influence of
metformin on the reduction of total and LDL-cholesterol
as well as triglycerides, body weight and blood pressure in
patients treated with metformin may positively affect cardiac
muscle performance [15]. Additionally, metformin-associated
enhanced fibrinolysis and reduced platelet hyper-aggregation
activity may reduce cardiovascular risk [16].
Lamanna et al. [17] stress that the reduction of
cardiovascular risk in metformin-treated patients with T2DM
seems to be duration-dependent, but according to Khurana

et al. [8] we have no published trails or registry data linking

metformin-associated LA with cardiac catheterization in
patients with T2DM. Even in those with renal impairment,
the data to support a causal relationship with LA is weak.
Moreover, there are doubts whether procedures requiring
iodinated contrast interfere with metformin usage.
Metformin is excreted unchanged by the kidneys and renal
function determines the clearance of the drug. The higher risk
of LA in patients with renal impairment taking metformin is
then connected with the accumulation of the drug. According
to insert package information metformin is contraindicated in
patients with creatinine clearance <60ml/min. In our study, the
average level of GFR for metformin users was >60ml/min.
Recent investigations aiming to establish pragmatic limits of
renal impairment in patients being considered for treatment
with metformin concluded that an estimated glomerular
filtration rate (GFR) of 30 mL/min should be an absolute
contraindication to the drug. Metformin may be continued
(or initiated) with GFR <60 ml/min or reviewed and reduced
(by 50% or to half-maximal dose) in patients with GFR <45
ml/min if close monitoring of renal function can be provided,
every 36 and 3 months, respectively [18]. In our study, we
found that about 51% of the patients had GFR <60 ml/min.
However, Kazory et al. [19] described a case of LA in a
55-year-old man treated with the recommended therapeutic
dose of metformin (2g daily) with creatinine clearance 91 ml/
min and coexisting hypertension. It is of great importance to
calculate GFR especially in older and obese patients because
serum creatinine can overestimate renal function in such cases
[20]. It is also highly doubtful whether old age per se should
be considered a contraindication to metformin. Gregorio et al.
[21] examined 84 T2DM subjects aged 70 years with poor
glycemic control, treated with different sulfonylureas and with
correct renal and liver biochemical function tests. Moreover, all
patients were free of severe macroangiopathy and respiratory
or congestive heart failure. After implementation of metformin,
marked improvement in the glycemic control was noted with
no significant modification in fasting blood lactate and a mild
increase in the post-prandial lactate peak.
Many authors underline that at least some contraindications
to metformin should be revised and then mitigated. It is also
believed that the degree of impairment of any organ that
could preclude metformin use should be well-defined. It will
allow re-evaluating the contraindications to this drug and will
enable more physicians to prescribe proper treatment within
guidelines. A growing body of clinical experience shows that
benefits from metformin-based treatment in most patients with
T2DM and contraindications outweigh the potential risks.
Most often it is postulated that chronic renal failure (as long
as GFR >40 ml/min), chronic heart failure (NYHA stages I
and II), old age per se or even discontinuation of metformin
therapy 2 days before surgery and intravenous contrast medium
administration should be removed from the label [22,23].
Nye and Herrington suggest that metformin should always
be avoided in patients whose renal function is deteriorating

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Kosmalski M et al.

acutely and in those patients in whom oxygenation, tissue

perfusion or liver function are severely compromised [24].
However, in patients with T2DM and stable chronic kidney
disease, clinicians are doing their patients a disservice by
prematurely and unnecessarily withdrawing metformin
treatment. In the latest issue of Diabetologia, Panossian et al.
[25], report severe deterioration of glycemic control (an increase
in HbA1c by 3% from baseline within 3-12 months) after
too rash withdrawal of this drug. Metformin was discontinued
because of concern about renal and cardiac function, hepatic
dysfunction or side effects. After careful analysis whether
metformin was truly contraindicated the authors of that report
decided to re-introduce the drug. A significant improvement of
glycemic control and good tolerability after re-introduction of
metformin was observed.

CONCLUSIONS
Althought off-label prescribing is legal and common, it is often
done in the absence of adequate supporting data. In our study
we did not observe any serious adverse effects of metformin
even in patients who had simultaneously as many as several
organ dysfunctions considered as contraindications to this
agent. Therefore, in accordance with others we suggest that
the indications for metformin usage should be reconsidered.
Metformin dosage must be individualized on the basis of
both effectiveness and tolerance, while not exceeding the
maximum recommended daily intake. However, keeping in
mind that unlicensed use of metformin may increase the risk
of serious adverse effects, every patient with T2DM receiving
metformin must have the opportunity to visit his/her medical
doctor frequently and be carefully monitored. Physicians who
prescribe metformin should mandatorily provide appropriate
counseling for patients who receive this drug and be made
aware that they may be liable for deviating from the standard
of care of the patients medical condition.

ACKNOWLEDGEMENTS
This study was supported by grant number 503/0-077-09/503-01
from the Medical University of Lodz, Poland.

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