Rev. Med. Chir. Soc. Med. Nat., Iaşi – 2013 – vol. 117, no. 4

PHARMACY UPDATES

1035

METFORMIN INDUCED LACTIC ACIDOSIS –

PARTICULARITIES AND COURSE

Anca-Monica Strugaru1, Gina Botnariu

3, Luminita Agoroaei

2,

Ioana-Cezara Grigoriu1,Elena Butnaru

2

University of Medicine and Pharmacy “Grigore T. Popa”- Iași Faculty of Pharmacy

1. Ph.D. student

2. Discipline of Toxicology

Faculty of Medicine

3. Discipline of Diabetes, Nutrition and Metabolic Diseases

METFORMIN INDUCED LACTIC ACIDOSIS – PARTICULARITIES AND COURSE (Ab-

stract): Diabetes mellitus is a widespread disease with many serious chronic complications. An

improvement in the oral antidiabetic medication in respect to its mechanism of action and toxi-

cology was needed in order to have effective therapies with high compliance and minimum

side effects. In this context, metformin is a widely used oral antidiabetic drug, which, through

its mechanism of action, has no risk of hypoglycemia. However, a rare but serious side effect

of biguanides is lactic acidosis. This paper presents a number of 13 cases of metformin-

associated lactic acidosis, which outline the circumstances triggering the adverse event and the

clinical therapeutic measures applied in the poisoned patients. The main situations that favor

metformin-associated lactic acidosis are renal impairment and tissue hypoxia, and the interven-

tion is adapted to the particular patient condition and symptoms, such as marked hypotension

and cardiac arrest. Although there are commonalities in describing the consulted patients, the

final prognosis is not dependent on the dose or metformin plasma levels, but rather on the asso-

ciated pathologies and medication. Keywords: DIABETES MELLITUS, METFORMIN,

LACTIC ACIDOSIS, RENAL IMPAIRMENT, HYPOXIA

Diabetes is probably one of the first ill-

nesses known to man. It was mentioned for

the first time in Egyptian manuscripts 3000

years ago, and in 1988 type 2 diabetes was

described as a component of the metabolic

syndrome. It represents one of the most

common forms of diabetes, characterized

by hyperglycemia, insulin resistance and

insulin deficiency. This illness results from

the interaction of genetic, social and behav-

ioral risk factors.

It is estimated that, in the year 2011, 366

million people had diabetes. This number is

thought to rise up to 552 by 2030. For the

same year, 2010, it is stated that the number

of deaths attributed to diabetes at a global

level is around 3.96 million for 20-79 age

group that is roughly 6.8% of the global

mortality rates for all age categories (1).

Metformin, a biguanide compound with

antidiabetic action, was first described in

the literature in 1922 by Werner and Bell,

as a product in the synthesis of N, N-

dimetilguanidine. In 1929, researchers

Slotta and Tschesche observed the sub-

stance to lower blood glucose in rats, and

they described the substance as the most

effective biguanide compound of the ones

Anca-Monica Strugaru et al.

1036

they studied (2).

Metformin has been accepted as an an-

tihyperglycemic agent in England in 1958,

in Canada in 1972, and in USA in 1995.

Currently, metformin is the first-line drug

in patients with type 2 diabetes who do not

have specific contraindications. Only in

2005 more than 42 million prescriptions for

metformin were issued in the United States

(3).

Besides its use in diabetic patients, met-

formin is also effective in polycystic ovary

syndrome and is being researched as an

antiviral and anticancer adjuvant.

Metformin activates an important en-

zyme called protein kinase AMP-activated

(AMPK), which plays an essential role in

body energy balance by regulating the

metabolism of carbohydrates and lipids.

Latest researches show that metformin

inhibits mitochondrial respiration by acti-

vating AMPK and the synthesis of fatty

acids. Metformin improves hyperglycemia

by reducing insulin resistance and plasma

insulin levels in the fasting state.

Known side effects of metformin in-

clude abdominal discomfort, nausea, vom-

iting, diarrhea, constipation, flatulence,

indigestion, heartburn (4). Another adverse

effect that may occur in long term metfor-

min administration is vitamin B12 deficien-

cy. Studies confirm that metformin can

cause malabsorption of vitamin B12 and

thus lower serum levels of this vitamin (5).

Lactic acidosis is a rare but serious ad-

verse effect of metformin associated with

its therapeutic use and overdose (6).

Lactic acidosis can be classified as fol-

lows: Type A (associated or caused by

inadequate oxygen transport to tissues) and

Type B (with adequate oxygen transport to

tissues). Type B has 3 sub-categories: B1 -

lactic acidosis associated with a disease

(eg, diabetes, asthma etc.), B2 - lactic aci-

dosis caused by drugs or toxins (e.g., cya-

nide, metformin, epinephrine, etc.), B3 -

lactic acidosis caused by congenital meta-

bolic disorders.

Depending on the cause, hyper-

lactatemia is defined as lactate levels be-

tween 2 and 5 mmol/L, although it is men-

tioned that lactic acidosis is present when

lactate levels are above 5 mmol/L and arte-

rial pH is lower than 7.35. These defini-

tions can however be arbitrary (7).

The lactate is the final product in anaer-

obic metabolism (it represents the product

obtained from the reduction of pyruvate by

lactate dehydrogenase enzyme). It is initial-

ly obtained in skeletal muscles, intestine,

brain and circulating erythrocytes, with a

production of approximately 1 mmol/kg/h.

The healthy liver takes the largest part of

the lactate and recycles it through three

main pathways: conversion to glucose (Co-

ri cycle), pyruvate oxidation, which can

then be oxidized to CO2 (Krebs cycle), and

transamination to alanine. The reduced

oxygen transport to tissues and cells cause

damage in oxidative phosphorylation, with

increasing intracellular amounts of NADH,

cofactor in the conversion of pyruvate to

lactate. Due to the close connection with

anaerobic metabolism the lactate was con-

sidered to be the end product of glycolysis

due to hypoxia (7).

Risk factors for the development of

metformin-associated lactic acidosis, such

as kidney failure, pre-existing heart dis-

ease, chronic lung injury with hypoxia, and

congestive heart failure, are usually con-

sidered contraindications to metformin

therapy. Age may be associated with de-

creased renal functions and the increase of

co morbidities (8). Figure 1 outlines the

mechanism of lactic acidosis production, in

Metformin induced lactic acidosis – particularities and course

1037

particular circumstances.

In patients who develop severe lactic

acidosis the symptoms are characteristic:

agitation, confusion, absent corneal reflex-

es, fixed dilated pupils, lethargy, convul-

sions, coma, and ultimately death (10).

Fig. 1. Lactic acidosis and the circumstances

which may increase the risk associated with metformin therapy (9)

We analyzed 13 cases of acute metfor-

min poisoning associated with lactic acido-

sis reported in the literature.

The circumstances that led to lactic aci-

dosis are presented in Table I. This severe

adverse effect also occurred in attempted

suicide by drug overdoses and chronic

administration to treat hyperglycemia.

Also, metformin-associated lactic acidosis

was present both in patients with or without

renal impairment. With regard to associated

medication, incriminated in the develop-

ment and/or worsening of metformin-

induced adverse effects, a definite link has

been established in the case of creatine co

administration (11).

The most frequent symptom of metfor-

min poisoning is gastrointestinal upset

when nausea, vomiting, diarrhea, ab-

dominal cramps, anorexia, epigastric dis-

comfort and pain, and loss of appetite oc-

cur. The occurrence of lactic acidosis caus-

es lethargy, confusion, dyspnea, hypother-

mia, hypotension, and hemodynamic insta-

bility. Table II lists all clinical observations

in patients with acute metformin poisoning.

The laboratory parameters reported for

acute metformin poisoning illustrate the

presence and course of lactic acidosis from

the time of diagnosis to the end of drug

treatment and hemodialysis. Table III

shows the evolution of laboratory values in

the patients. The therapeutic approach en-

tailed the normalization of acid-base im-

balance, the acceleration of lactate metabo-

lism process, the elimination of metformin,

simultaneously treating related diseases.

Following the patients evolution, metfor-

min-associated lactic acidosis proved re-

versible when diagnosis and initiation of

treatment are immediate so that therapeutic

measures to be effective.

Anca-Monica Strugaru et al.

1038

TABLE I

Particularities of triggering metformin induced lactic acidosis

Reference Treatment

with metformin Associated pathology Associated medication

Van Velzen,2008 (12) chronic treatment renal failure caused

by diclofenac various drugs

Saidi,2010 (11) 500 mg x 2/day * creatine

Yang,2009 (13) suicide attempt diabetic nephropathy *

Van Sloten,2012 (14) chronic treatment * *

Kreshak,2010 (15) chronic treatment

coronary heart disease,

peripheral vascular disease, hypertension,

hypercholesterolemia,

osteoarthritis

lisinopril, aspirin, metoprolol, clopidogrel, acetaminophen,

hydrocodone

Akoglu,2011 (16) suicide attempt:

144.5 g * *

Browers,2009 (17) chronic treatment total colectomy, acute renal

failure enalapril, atorvastatin, glicazid

Dell' Aglio,2010 (6) overdose: 75-100 g * *

Perrone,2011 (3) overdose * overdose of: risperidone, sertraline,

hydrochlorothiazide, glyburide

Perrone,2011 (3) chronic treatment multiple pathology,

final stage renal disease

amiodarone, clonidine,

valsartan, gabapentin, glyburide,

furosemide, atorvastatin, lisinopril,

amlodipine, omeprazole

Perrone,2011 (3) chronic treatment hypertension,

final stage renal disease *

Al-Makadma,2010 (18) suicide attempt:

40-45 g * *

Kim,2008 (19) overdose: 30 g hypertension carvedilol (Dilatrend®)

* Not specified.

TABLE II

The symptoms of acute metformin poisoning associated with lactic acidosis

Reference

Symptoms Other

symptoms gastro-

intestinal renal

central nerv-

ous system

cardio-

vascular Lungs

Van Velzen,2008

(12) * * confusion * * loss of appetite

Saidi,2010 (11) * oliguria and

then anuria

drowsiness,

malaise

cardiac

arrest

pulmonary

edema anorexia

Yang,2009 (13) * oliguria lethargy * * loss of appetite,

hypothermia

Van Sloten,2012

(154) * * delirium * * acute prostatitis

Kreshak,2010 (15) * * * * *

bilateral vision

loss without

associated pain,

hypothermia

Akoglu,2011 (16) * * * * * Hypothermia

Browers,2009 (17)

nausea,

vomiting,

abdominal

pain,

diarrhea

* * * * *

Dell' Aglio,

2010 (6) * * lethargy * * *

Perrone,2011 (3) * * lethargy * * *

Perrone,2011 (3) * * * *

Kussmaul

type breath-

ing, diffuse

rales

in the chest

weakness,

dry mucous

Perrone,2011 (3) * * * * dyspnea *

Al-Makadma,2010

(18) * *

marked

irritability,

deterioration of

consciousness

* * *

Kim,2008 (19) * * irritability * * *

* Not specified.

Metformin induced lactic acidosis – particularities and course

1039

TABLE III

The recorded laboratory values in patients with acute metformin intoxication

Synthesizing the data in the literature it

comes out that metformin-associated lactic

acidosis is a very rare complication when

no co morbidity is present (chronic kidney

disease, myocardial infarction, sepsis,

which can cause lactic acidosis even in the

absence of metformin use).

Associated pathologies and particular

conditions were encountered in case of:

creatine administration, kidney damage

Anca-Monica Strugaru et al.

1040

caused by associated medication (e.g.,

diclofenac), kidney failure. The literature

mentions that approximately 25% of the

patients treated with metformin have at

least one contraindication for this drug,

contraindication that may favor the occur-

rence and even worsen the evolution of a

lactic acidosis case (13, 20). This compli-

cation may occur both in case of metformin

overdose and during chronic treatment with

normal therapeutic doses. No correlations

were found between metformin plasma

levels and the severity of lactic acidosis

poisoning (20). This supports the im-

portance of associated pathology and clear

contraindications in the administration of

metformin.

It is known that tissue hypoxia and kid-

ney disease are common factors for lactic

acidosis. Moreover, patients suffering from

diabetes may have an ineffective glycemic

control with high levels of glycated hemo-

globin which causes kidney damage due to

diabetic nephropathy. Thus, attempting an

effective metformin treatment in the pres-

ence of early chronic complications of

diabetes can have serious consequences.

According to studies, even with prompt

intervention, the mortality rate of lactic

acidosis ranges between 60% and 90%

(11).

Some studies have even pointed out a

biological explanation for metformin-

associated lactic acidosis. The genetic

changes that may occur in the OCT1 pro-

tein may affect the pharmacokinetics of

metformin. OCT1 or the organic anion

transporter 1 facilitates the hepatic uptake

of metformin and a single polymorphic

nucleotide of OCT1 may be associated with

increased intracellular levels of metformin,

and therefore an increased risk of develop-

ing metabolic acidosis at therapeutical

plasmatic concentrations (14).

Intervention regimens for metformin as-

sociated lactic acidosis include the intrave-

nous administration of sodium bicarbonate.

It aims to correct acidosis and restore fluid

and electrolyte balance, but sodium bicar-

bonate can present some disadvantages: the

occurrence of hypervolemia caused by

sodium, the aggravation of intracellular

acidosis, and the decomposition of oxy

hemoglobin.

Hemodialysis is another treatment used

in metformin-associated lactic acidosis, but

since metformin has a large volume of

distribution, hemodialysis only removes a

small amount of the drug; this therapeutic

approach is effective especially when cor-

recting the serious effects associated with

acidosis. When initiating hemodialysis a

rebound effect was observed. Metformin is

stored in the intestine and erythrocytes and

produces and increases the serum lactate

concentration. Continued hemodialysis is

recommended when subsequently serum

lactate levels normalize and lactic acidosis

is corrected.

Metformin itself does not cause hypo-

glycemia but the treatment plan typically

includes an antidiabetic sulfonylurea. The

situations in which metformin alone can

cause hypoglycemia are: fasting, sustained

physical exercise, kidney failure. Hypogly-

cemia may occur under these conditions

and can be corrected by administering in-

travenous glucose. However, some authors

assert that the administration of glucose

may worsen lactic acidosis because intra-

cellular glucose metabolism is directed

towards the formation of lactate.

In addition, it was found that insulin has

beneficial effects in metformin-associated

lactic acidosis, but blood glucose levels

should be monitored closely (17).

Metformin induced lactic acidosis – particularities and course

1041

Impaired vision in metformin therapy is

also very rare, but reversible by optimal

intervention. It is explained by the occur-

rence of metformin-associated lactic acido-

sis, which causes damage to retinal cells,

whose function may be pH dependent (15).

Blood pH adjustment resulted in the re-

sumption of normal function and return of

normal vision.

Hypothermia is another symptom seen

in metformin-associated lactic acidosis and

it is also reversible. It is probably related to

severe hypoglycemia and an acid-base

imbalance in the blood.

It must be pointed out that according to

studies metformin-associated lactic acido-

sis is rare, with a frequency of 1 to 9 pa-

tients per 100,000 people (6). If with

chronic metformin administration lactic

acidosis is an exceptional phenomenon, its

occurrence being attributed especially to

present co morbidities, in the cases of acci-

dental or suicidal metformin overdoses,

lactic acidosis is very likely to occur, and

the state of the patient and the severity of

poisoning are differentiated on a case to

case basis.

The minimum diagnostic tests in case of

metformin overdose include the determina-

tion of serum electrolytes, serum bicar-

bonate, renal function tests, arterial blood

gas test to determine pH, and determination

of blood glucose and serum lactate. Fur-

thermore, all patients with acidosis should

be tested for possible salicylates intoxica-

tion, to exclude this variant (6).

In conclusion, the phenomenon of lactic

acidosis may be associated with metformin

administration, but there are a variety of

special conditions that have an influence on

its occurrence and outcome. Thus, we can

conclude that there is no correlation be-

tween the amount of ingested metformin,

plasma metformin and lactate levels, and

the degree of patient impairment and out-

come.

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INHALED CORTICOSTEROIDS AND PNEUMONIA

Inhaled corticosteroids (ICS) are used for treatment of chronic bronchitis, emphysema and

asthma. But prolonged treatment increases the risk of associated pathologies: vitamin D de-

ficiency, bone fractures, type 2 diabetes and pneumonia. A study, conducted by Dean Eurich

and colleges during 5 year, has showed an increased risk of recurrent pneumonia for elderly

patients which used ICS in the treatment of chronic obstructive pulmonary disease. The

study has included 653 recurrent pneumonia cases and 6244 controls and show that 14% of

current ICS users had developed recurrent pneumonia compared to 9% never -users. These

findings suggest that ICS use increases the risk of recurrent pneumonia with 90% for the pa-

tients who survived after an initial episode of pneumonia. These data are useful in establish-

ing optimal regimens, depending on patient characteristics (Eurich DT, Lee C, Marrie TJ et

al. Inhaled Corticosteroids and Risk of Recurrent Pneumonia: A Population-Based, Nested

Case-Control Study. Clinical Infectious Diseases, 2013; DOI: 10.1093/cid/cit472).

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