Kos Maghhlski 2012

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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 elderlytype 2 diabetes mellitus (T2DM) patients

Department of Internal Disease, Diabetology and Clinical Pharmacology, Medical University of Lodz, Zgierz, Poland

Kosmalski M, Drozdowska A, Sliwinska A, Drzewoski J*

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

* CORRESPONDING AUTHOR:Department of Internal Disease, Diabetology and Clinical Pharmacology,Medical University of Lodz,Parzeczewska 35,95-100 Zgierz, PolandTel./Fax: +48 42 714 45 51,e-mail: [email protected] (Jozef Drzewoski)

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

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 life-

threatening lactic acidosis (LA), may substantially increase

[2].


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

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 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

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

BMI (kg/m2) 30.48 5.95 29.47 4.87 P=0.123

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

Diastolic blood pressure (mmHg) 78.56 15.01 75.18 11.14 P=0.033

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

Urea acid (umol/l) 365.70 120.73 354.37 121.79 P=0.443

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

Table 1. Characteristics of the patients with contraindications to metformin who were (Group A) and who were not treated with the

drug (Group B).

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.

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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).Chi-

square tests (Tab. 2)were used to assess the distributions of

contraindications to metformin. A value of p


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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 innon-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 cardiovascularrisk. 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 thisdrug 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.

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


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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 receivingmetformin 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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