Download Metformin Associated Lactic Acidosis

Metformin Associated Lactic Acidosis
Jun-Ki Park
9/6/11
“Probably the most common mechanism by which
metformin elevates blood lactate is by inducing
catecholamine release in those who regulate or
prescribe it”
Peter W Stacpoole, Editorial, Diabetes Care 1998

Incidence: estimated 2-10 patients per 100,000 patients
receiving metformin per year.

MALA accounts for approximately 0.1-1% of total
patients admitted to ICU.

Life-threatening condition with mortality rate of 30-50%.

Nearly all of the reported cases of MALA have
occurred in individuals with both hemodynamic (e.g.
hypotension) and metabolic (e.g. liver or renal
disease) underlying causes of impaired lactate
metabolism.

Controversy remains whether the use of metformin
is a cause or a coincidence in lactic acidosis of DM
patients.
LA Rates in T2DM Before Introduction of
Metformin
Brown et al. Diabetes Care 1998
Biguinides
Pharmacokinetic Aspects of Metformin
Bioavailability
50–60 percent; absorbed mainly from the small intestine;
estimated absorption half-life, 0.9 to 2.6 hours
Plasma concentration Maximal, 1 to 2mg per milliliter (approximately105M) 1 to 2
hours after an oral dose of 500 to 1000 mg; negligible binding
to plasma proteins
Plasma half-life
Estimated at 1.5 to 4.9 hours
Metabolism
Not measurably metabolized
Elimination
About 90 percent is eliminated in urine in 12 hours;
multiexponential pattern involving glomerular
filtration and tubular secretion

Metformin has acid dissociation constant values (pKa) of
2.8 and 11.5 and, therefore, exists very largely as the
hydrophilic cationic species at physiological pH.

The pKa of 11.5 makes metformin a stronger base than
most other basic drugs with less than 0.01% unionized in
blood

The volume of distribution (Vd) has been reported to
range from 63 to 276 L after IV administration.

During dosage with 2000 mg metformin daily, Vd is
approximately 600 L. As approximately 50% is absorbed
the actual Vd during multiple dosage is about 300 L.
This large Vd indicates that there is considerable tissue
uptake of metformin.

Excretion of unchanged drug in urine is the major mode of
elimination of metformin. No metabolites of metformin have
been found in urine.

Metformin is a small molecule (165Da) which is not bound to
plasma proteins and, therefore, is readily filtered at the
glomerulus.

The low lipid solubility of metformin should lead to negligible
passive resorption.

Metformin is a substrate for several transporters in the kidney
Graham et al. Clin Pharmacokinet 2011
Pathomechanism of MALA

Metformin promotes the conversion of glucose to lactate
in the splanchnic bed of small intestine

Intracellular redox potential shifts from aerobic to
anaerobic metabolism

Metformin inhibits hepatic gluconeogenesis from lactate,
pyruvate, alanine, resulting in additional lactate and
substrate for lactate production. (mainly by decreased
pyruvate carboxylase activity, a rate limiting enzyme in
the formation of glucose from lactate)
Owen et al. Biochem J 2000
Owen et al. Biochem J 2000
X
Does plasma metformin level predict lactate
level / mortality?
Lalau et al. Diabetes Care 1998
Seidowsky et al. Crit Care Med 2009

Highest arterial levels of lactate were not
consistently a/w high plasma concentrations of
metformin in this series of patients.

Patient’s underlying hemodynamic condition, not
the degree of metformin accumulation, is the
main determinant of marked hyperlactatemia.

Multivariate analysis performed to determine the
factors independently associated with mortality,
with the following variables:
- age, arterial blood lactate, pH, LODS score
and PT activity.

The only variable significantly associated with
mortality in this multivariate model was PT
activity at admission (p < 0.0001)
Treatment

Optimal treatment modality for MALA is controversial and relies on
nonspecific supportive measures:
- Gastrointestinal decontamination for acute ingestions; active
charcoal.
- Securing airway, breathing and circulation
- For patients with profound acidosis (pH <7.10), consider
sodium bicarbonate infusion; e.g. 1-2meq/kg IVP, then 3 amps
bicarb in 1L D5W at 250cc/hr)
- For pt with profound acidosis, renal disease, or critical illness,
HD/CRRT. Hemodialysis will correct metformin-associated acidbase disturbance and increase metformin clearance.
Hemodialysis

In the Seidowsky study, of all patients, 31 were treated by
HD, always initiated in the first 12 hours after admission
in the ICU.

Sequential measurements of plasma metformin levels
during HD showed that in 85% of patients, a cumulative
HD duration of 15 hours was a/w the return of
metformin level to normal therapeutic values.
Seidowsky et al. Crit Care Med 2009
Seidowsky et al. Crit Care Med 2009
Exclusion Criteria for the Use of
Metformin

Renal impairment: plasma creatinine values 1.5 mg per deciliter (132 mmol
per liter) for men and 1.4 mg per deciliter (124 mmol per liter) for women

Cardiac or respiratory insufficiency that is likely to cause central hypoxia
or reduced peripheral perfusion

History of lactic acidosis

Severe infection that could lead to decreased tissue perfusion

Liver disease, including alcoholic liver disease, as demonstrated by
abnormal liver-function tests

Alcohol abuse with binge drinking sufficient to cause acute hepatic toxicity

Use of intravenous radiographic contrast agents
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