Analytic Review

Journal of Intensive Care Medicine

1-14
Review of Biguanide (Metformin) Toxicity ª The Author(s) 2018
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DOI: 10.1177/0885066618793385
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George Sam Wang, MD1,2 and Christopher Hoyte, MD1,3

Abstract
In the 1920s, guanidine, the active component of Galega officinalis, was shown to lower glucose levels and used to synthesize
several antidiabetic compounds. Metformin (1,1 dimethylbiguanide) is the most well-known and currently the only marketed
biguanide in the United States, United Kingdom, Canada, and Australia for the treatment of non-insulin-dependent diabetes
mellitus. Although phenformin was removed from the US market in the 1970s, it is still available around the world and can be
found in unregulated herbal supplements. Adverse events associated with therapeutic use of biguanides include gastrointestinal
upset, vitamin B12 deficiency, and hemolytic anemia. Although the incidence is low, metformin toxicity can lead to hyperlactatemia
and metabolic acidosis. Since metformin is predominantly eliminated from the body by the kidneys, toxicity can occur when
metformin accumulates due to poor clearance from renal insufficiency or in the overdose setting. The dominant source of
metabolic acidosis associated with hyperlactatemia in metformin toxicity is the rapid cytosolic adenosine triphosphate (ATP)
turnover when complex I is inhibited and oxidative phosphorylation cannot adequately recycle the vast quantity of Hþ from ATP
hydrolysis. Although metabolic acidosis and hyperlactatemia are markers of metformin toxicity, the degree of hyperlactatemia and
severity of acidemia have not been shown to be of prognostic value. Regardless of the etiology of toxicity, treatment should
include supportive care and consideration for adjunct therapies such as gastrointestinal decontamination, glucose and insulin,
alkalinization, extracorporeal techniques to reduce metformin body burden, and metabolic rescue.

Keywords
biguanide, metformin, phenformin, metabolic acidosis, hyperlactatemia, lactic acidosis

Introduction 1960s but is no longer available.7 We will focus on the toxicity

Biguanides are a class of drugs and chemicals based on the
biguanidine molecule (Figure 1). These compounds were ini-
tially derived from the Galega officinalis (French lilac or goat’s
rue) plant.1 In the 1920s, guanidine, the active component of
Galega officinalis, was shown to lower glucose levels and used
to synthesize several antidiabetic compounds. Metformin (1,1
dimethylbiguanide) is probably the most well-known bigua-
nide. Currently, it is the only marketed biguanide in the United
States, United Kingdom, Canada, and Australia for the treat-
ment of non-insulin-dependent diabetes mellitus (NIDDM).2,3
Other biguanides include antidiabetic agents phenformin (phe-
nylethyl biguanide) and buformin (1-butylbiguanide) and the
antimalarial proguanide (N-(4-chlorophenyl)-N-(isopropyl)-
imidodicarbonimidic diamide). Phenformin was marketed in
the United States in 1950s. It was removed from the market
in the late 1970s because there was a high incidence of hyper-
lactatemia and metabolic acidosis associated with its therapeu-
tic use.4,5 Proguanil and chlorproguanil are commercially
available antimalarials marketed as combination products with
atovaquone and dapsone, respectively. Polyaminopropyl
biguanide, chlorhexidine, alexidine, and polyhexanide are
examples of biguanides used as antiseptics and disinfectants.6
Moroxydine was briefly used as a treatment for influenza in the
of metformin and phenformin in this review.
Available Formulations, Therapeutic Dosing,
and Pharmacokinetics
Metformin is available as a stand-alone medication in an
immediate-release or extended-release tablet and liquid formu-
lation. It is also available as a combination product with other
antihyperglycemic and antihyperlipidemic medications includ-
ing pioglitazone, rosiglitazone, sitagliptin, linagliptin, saxa-
gliptin, glipizide, and repaglinide.8,9 The US Food and Drug
Administration (FDA)-labeled indication for metformin is type
2 diabetes mellitus, but also used for hyperinsular obesity,
1
University of Colorado Anschutz Medical Campus, Aurora, CO, USA
2
Children’s Hospital Colorado, Aurora, CO, USA
3
University of Colorado Hospital, Aurora, CO, USA
Received June 26, 2018. Received revised July 16, 2018. Accepted July 18,
2018.
Corresponding Author:
George Sam Wang, University of Colorado at Denver—Anschutz Medical
Campus, 13123 E 16th Ave B251, Aurora, CO 80401, USA.
Email: george.wang@childrenscolorado.org
2 Journal of Intensive Care Medicine XX(X)
Figure 1. Structures of biguanides.
hypersecretion of ovarian androgens, polycystic ovary syn-
drome, and weight gain induced by antipsychotic therapy.1,8
The recommended oral metformin dosing for adults is 500 to
2000 mg daily. Metformin has an oral bioavailability of 40% to
60% after absorption in the small intestine, with complete gas-
trointestinal absorption by 6 hours, and a time to peak concen-
tration between 4 to 8 hours.10 It is rapidly distributed and has
minimal protein binding. Therapeutic blood or plasma metfor-
min concentrations are 0.5 to 1 mg/L in a fasting state and 1 to 2
mg/L after a meal and are reached within 24 to 48 hours.9,10
Metformin does not undergo hepatic metabolism. Approxi-
mately 90% of the absorbed dose is renally excreted involving
glomerular filtration and tubular secretion. The plasma elimi-
nation half-life is 4 to 8.7 hours, which can be prolonged in
patients with renal insufficiency. In blood, the elimination half-
life is approximately 17.6 hours, suggesting that the erythro-
cyte mass may be a compartment of distribution. The FDA does
not recommend metformin use with creatinine concentrations
1.5 mg/dL (132 mmol/L) in men and 1.4 mg/dL (123 mmol/L)
in women and is contraindicated in patients with a glomerular
filtration rate <50 mL/min.9,10 The Canada Diabetes Associa-
tion, the National Institute for Health and Clinical Excellence,
and the Australian Diabetes Society recommend that an esti-
mated glomerular filtration rate 29 mL/min/1.73 m2 should
be a contraindication for metformin use.11,12
Phenformin is available in Europe, South America, and Asia
and can be obtained through Internet or mail orders.13-19
Despite not being available in the US market, phenformin and
buformin are still available in several countries in Europe,
South America, and Asia and can be found in unregulated
herbal supplements.13-19 In an analysis of 29 adulterated herbal
antidiabetic products in Hong Kong, 18 of them contained
phenformin.19 When commercially available, the therapeutic
dose is 50 to 200 mg/d. The pharmacokinetics of phenformin
are different from metformin. Phenformin is more lipophilic
and undergoes some hepatic metabolism with 33% eliminated
Wang and Hoyte
unchanged. Phenformin is 19% protein bound and is slower to
clear with an elimination half-life of approximately 11 hours,
and the majority of the drug in the therapeutic setting is elim-
inated within the first 24 hours.20,21
Mechanism of Action in Therapeutic Dosing
In therapeutic doses, metformin appears to decrease blood
glucose levels by several mechanisms. Metformin enhances
suppression of gluconeogenesis by insulin and reduces
glucagon-stimulated gluconeogenesis.1 Metformin can posi-
tively affect insulin receptor phosphorylation and tyrosine
kinase activity. Metformin can also increase translocation of
the Glucose Transporter (GLUT)-1 and GLUT-4 isoforms
of glucose transporters as well as prevent the development of
insulin resistance in hepatocytes and adipocytes.1,5 By increas-
ing hepatic insulin sensitivity, metformin reduces basal hepatic
glucose output and fasting glucose concentrations.22,23 The
other antidiabetic biguanides, phenformin, and buformin have
similar mechanisms of action as metformin.
Adverse Events Associated With Therapeutic
Dosing
Adverse events associated with therapeutic use of all bigua-
nides include gastrointestinal symptoms (eg, nausea, vomiting,
diarrhea, and abdominal pain).8,9 Reports of acute hepatitis and
cholestasis are rarely reported with metformin.24-28 Although
there was an apparent temporal relationship to hepatotoxicity
and the initiation of metformin in case reports, all these patients
had significant comorbidities (eg, type 2 diabetes and hyper-
tension), along with use of other potentially hepatotoxic med-
ications including statins and angiotensin-converting enzyme
inhibitors. None of these patients were rechallenged with met-
formin, and all reported cases resolved with discontinuity of all
their medications.
Metformin has been associated with malabsorption syn-
dromes resulting in electrolyte abnormalities and vitamin B12
deficiency.29-40 Associated diarrhea can lead to hypomagne-
saemia, hypocalcemia, and hypokalemia.32,33 Vitamin B12
deficiency can present clinically as megaloblastic anemia or
neuropathies. The mechanism of vitamin B12 deficiency is
unclear but is proposed to be multifactorial including altera-
tions in gut flora, motility, competitive inhibition of absorption,
or impairing calcium-dependent membrane actions on the ter-
minal ileum.34 A case–control study concluded that each gram
per day metformin dose increment conferred an odds ratio of
2.88 and duration greater than 3 years of use conferred an odds
ratio of 2.39 for developing vitamin B12 deficiency.36 When
vitamin B12 concentrations in diabetics who received metfor-
min were compared to diabetics who received sulfonylureas,
vitamin B12 concentrations were lower in patients receiving
metformin as early as 4 months of initiating therapy.30 Vitamin
B12 deficiency has responded to B12 supplementation but may
necessitate discontinuation of metformin. Recommendations
for patients receiving metformin therapy who may be at high
3
risk for B12 deficiency include empiric vitamin B12 supplemen-
tation, monitoring B12 concentrations and/or blood counts for
anemia, or regular examinations evaluation for neuropathy.34
There are also case reports of vitamin B12 deficiency associated
with phenformin therapy.38-40
Metformin-associated hemolytic anemia is rarely
reported.41-48 The majority of case reports are associated with
therapeutic metformin dosing, and one case report in the setting
of an overdose.48 There are 2 case reports where hemolysis
recurred following metformin rechallenge.42,47 Metformin-
associated hemolytic anemia has been reported in patients with
comorbidities such as leukemia44 and glucose-6-phosphate
dehydrogenase deficiency.41,43,45 Serologic data suggest met-
formin hemolytic anemia can be immunologically
mediated.42,44,46,47 Although metformin-associated hemolytic
anemia can be fatal,46 patients usually recover with supportive
care and discontinuation of metformin.
Epidemiology
In 2009, 37% of all Medicare beneficiaries with diabetes were
on metformin therapy as part of their care, higher than insu-
lins, sulfonylureas, and thiazolidinediones.49 Despite this pre-
valent use of metformin, the reported rate of “lactic acidosis”
is low. Salpeter and colleagues evaluated 194 comparative
trials or observation cohort studies that evaluated metformin
therapy alone or in combination with other treatments for at
least 1 month.50 They found no cases of “lactic acidosis” in
36 893 patient-years in the metformin group or 30 109 patient-
years in the nonmetformin group. The estimated true incidence
of “lactic acidosis” in the metformin and the nonmetformin
was 8.1 and 9.9 per 100 000 patient-years, respectively.50 The
same authors published a Cochrane Review several years later
that included 347 comparative trials and cohort studies in
patients who received metformin for at least a month com-
pared with placebo or other glucose-lowering therapy.51 There
were no cases of fatal or nonfatal “lactic acidosis” in 70 490
patient-years of metformin use or in 55 451 patient-years in
the nonmetformin group. Their estimate of the incidence of
“lactic acidosis” per 100 000 patient-years was 4.3 cases in the
metformin group and 5.4 cases in the nonmetformin group.
However, the interobserver agreement was low on whether
metformin was the most important causative factor in cases
of “lactic acidosis,” and passive reporting in trials similar to
those reviewed may be limited due to underreporting.
Chan and colleagues performed a literature search to find
metformin-associated “lactic acidosis” cases that were reported
worldwide: 31 cases in the United Kingdom over 34 years (19
were fatal), 16 cases in 14 years in Sweden, 2 nonfatal cases in
Switzerland over 5 years, 73 cases in France in 8 years (nearly
half were fatal), and none in Canada in 10 years.2 The reported
incidence of metformin-associated “lactic acidosis” was 3
cases per 100 000 patient-years. However, these investigators
did not qualify their search results and inclusion criteria for
analysis. There was no determination if the “lactic acidosis”
4 Journal of Intensive Care Medicine XX(X)
Figure 2. Biochemical pathways involved in metformin pathophysiology.
cases were associated with therapeutic or overdose setting, and
with most pooled data, it is subject to underreporting.
In contrast to “lactic acidosis” in the therapeutic setting,
regional poison centers review metformin-related toxicity in
both acute overdose and therapeutic settings. The Toxic Expo-
sure Surveillance System of the America Association of Poison
Control Centers reported a total of 10 958 526 total exposures
from 1996 to 2000, of which 4072 were metformin exposures.
Approximately 1% of metformin exposures led to severe
adverse events.52 From 2009 through 2013 (excluding 2010,
case fatalities were not reported), the American Association of
Poison Control Center National Poison Data System reported
21, 30, 30, and 39 fatality cases, respectively, where metformin
was noted to be at least contributory to the patient’s death.53-57
The incidence of phenformin-associated “lactic acidosis”
was reported to be much higher than metformin. Between
1965 and 1977, The Swedish Adverse Drug Reaction Commit-
tee reported 91 suspected adverse drug reactions to biguanides:
50 reports of “lactic acidosis” and 19 deaths with phenformin,
compared with one nonfatal case of “lactic acidosis” with met-
formin.58 In 1979, a registry in Finland estimated 1 in 2300 to
5700 patients taking phenformin therapeutically developed
“lactic acidosis,” compared to an estimated 1 in 40 000 to
80 000 in patients taking metformin or buformin.59 A review
of 330 cases in 1978 of biguanide-associated “lactic acidosis”
reported 86% of the cases were due to phenformin and 50% of
these patients died.60
Pathophysiology of Metformin Toxicity
Hyperlactatemia and metabolic acidosis are the hallmark of
biguanide toxicity, and it is often misrepresented as “lactic
acidosis,” that is, lactate production releases a proton and
causes acidosis. Biochemically, lactate production is always
accompanied by an equivalent appearance of hydrogen ion;
an increase in blood lactate concentration (hyperlactatemia)
does not result in excess hydrogen ions and would not contrib-
ute to the actual cause of acidosis. However, hyperlactatemia or
an increase in lactate to pyruvate ratio is a biochemical marker
for a decrease in aerobic metabolism (Figure 2). To better
understand this, we will briefly review the biochemistry and
metabolic pathways involved in lactate metabolism. This is
followed by a review and discussion for a mechanism of hyper-
lactatemia and metabolic acidosis during metformin toxicity.
In normal (aerobic) conditions, glycolysis generates 2 ade-
nosine triphosphate (ATP) molecules, while 2 molecules of
nicotinamide adenine dinucleotide (NADþ) are reduced to
NADH, primary source of cytosolic NADH. An intermediary
sequence is the oxidation of fructose 1,6-bisphosphate to gly-
ceraldehyde 3-phosphate and dihydroxyacetone phosphate
(DHAP). Dihydroxyacetone phosphate is rapidly and reversi-
bly isomerized by triosephosphate isomerase to glyceraldehyde
3-phosphate, which is oxidized to 1,3-bisphosphoglycerate
with the simultaneous reduction in NADþ to NADH; NADþ
must be regenerated for glycolysis to continue. Two major
Wang and Hoyte
cytosolic reduction–oxidation (REDOX) reaction shuttle sys-
tems, the glycerol 3-phosphate shuttle and the malate-aspartate
(MAL-ASP) shuttle, transport the electrons from cytoplasmic
NADH into the mitochondria. The glycerol 3-phosphate shuttle
is composed of cytosolic and mitochondrial isoforms of gly-
cerol 3-phosphate dehydrogenase (GPD). Cytoplasmic GPD
(cGPD) catalyzes the reduction in DHAP to glycerol 3-
phosphate, while one molecule of NADH is oxidized to
NADþ. Glycerol 3-phosphate is reoxidized back to DHAP
by mitochondrial GPD (mGPD), a flavin adenine dinucleotide
(FAD)-linked enzyme that transfers electron pairs to FADþ.
The resultant FADH2 transfers its electrons to the electron
carrier ubiquinone, which then enters the electron transport
chain as ubiquinol. The transport of electrons from cytosolic
NADH into mitochondria by the MAL-ASP shuttle, in contrast
with the glycerol 3-phosphate shuttle, is readily reversible and
is principally driven by the mitochondrial transmembrane elec-
trical potential gradient established by the proton pump of the
electron transport chain.61-63 The end process of aerobic meta-
bolism occurs when pyruvate is transported into the mitochon-
dria. Pyruvate is decarboxylated to acetyl-CoA in a reaction
catalyzed by pyruvate dehydrogenase complex with reduction
in NADþ to NADH and enters the citric acid cycle, which fuels
the electron transport chain by generating NADH and supply-
ing succinate to be oxidized to fumarate while FADþ is
reduced to FADH2; FADH2 effectively passes its electron onto
ubiquinone reducing it to ubiquinol and regenerates FADþ. As
electrons from NADH and FADH2 move along the electron
transport chain, hydrogen ions (Hþ) are pumped across the
inner mitochondrial membrane into the mitochondrial inter-
membrane space, creating a transmembrane electrochemical
potential that drives ATP production (ie, chemiosmosis).64
Normally, pyruvate, NADH, Hþ produced from substrate
flux through glycolysis, and products of ATP hydrolysis (ADP,
Pi, and Hþ) are predominantly consumed as substrates during
mitochondrial respiration. Oxidative phosphorylation recycles
vast quantities of Hþ for ATP synthesis, thereby maintaining a
virtually constant pH, and is the primary source of cellular
bioenergetics. When mitochondrial oxidative phosphorylation
is compromised (eg, complex I inhibition), there is a precipi-
tous decrease in ATP production, and in an attempt to sustain
cellular energy stores, ATP production becomes dependent on
glycolysis. As glycolysis intensifies, there is an increase in
glucose consumption, substrate flux to pyruvate, and reduction
in pyruvate to lactate in a reaction catalyzed by lactate dehy-
drogenase (LDH) with the oxidation of NADH to NADþ. A
conceptually important aspect of this catalytic reaction is lac-
tate (not lactic acid). When pyruvate is reduced to lactate, 2
electrons and a proton are removed from NADH, and a proton
is consumed from solution. There is no net Hþ released and a
proton is consumed each time a molecule of lactate is pro-
duced. Thus, the formation of lactate is not a source of net
Hþ and lactate does not cause or contribute to metabolic acido-
sis.65 The disposition of lactate is its entry into metabolism
through LDH by a REDOX-dependent reaction into the pyru-
vate pool.
5
In vitro and animal studies have shown metformin inhibits
mGPD but not cGPD at doses used to treat patients with
NIDDM, and at higher doses inhibits oxidative phosphoryla-
tion complex I of the mitochondrial electron transport
chain. 66-69 Inhibition of mGPD would halt the glycerol
3-phosphate shuttle, disrupt glyceraldehyde 3-phosphate oxida-
tion to DHAP, and increase the cytosolic REDOX state.
Gluconeogenesis becomes impaired as a result of decreased
DHAP and increased cytosolic NADH. The increase in cyto-
solic NADH is unfavorable for the oxidation of lactate to pyr-
uvate, thus decreasing the pyruvate pool for gluconeogenesis.
Lactate accumulates and hyperlactatemia is the result of the
inability of lactate to participate in its entry into metabolism
via the pyruvate pool. Tissues that normally rely on mitochon-
drial respiration for ATP (eg, skeletal muscle) would be the
dominant source of lactate production as cellular energetics
become dependent on accelerated anaerobic glycolysis when
mitochondrial function is compromised; major source of lac-
tate is nonhepatic in origin. Although hyperlactatemia may be
viewed as an imbalance between lactate production and lactate
utilization, the relative clinical importance of these factors
associated with hyperlactatemia is controversial. However,
there is little doubt that during severe acidosis, there is reduced
lactate uptake by the liver and the liver becomes a source of
lactate production. Both blood lactate and pyruvate production
have been observed to increase with a disproportionally greater
increase in lactate production, resulting in a significant increase
in lactate to pyruvate ratio during severe phenformin toxi-
city.70-74
Inhibition of complex I compromises oxidative phosphory-
lation by impeding electron transport, slows NADþ regenera-
tion, and retards the citric acid cycle and thus decreases the
availability of succinate and consequently electrons being
transferred to FADþ and processing through complex II of the
electron transport chain. As electron transport is slowed, recy-
cling of Hþ becomes inept and the mitochondrial transmem-
brane falters resulting in paralysis of the MAL-ASP shuttle and
decreased ATP production. A dysfunctional MAL-ASP shuttle
also slows the removal of cytoplasmic NADH and exacerbates
the high cytoplasmic REDOX state created by mGPD inhibi-
tion, which further favors the reduction of pyruvate to lactate.
A compromised oxidative phosphorylation will not be able to
keep pace with the demands of cellular energetics and it
becomes dependent on glycolysis for ATP production. Glyco-
lytic ATP production is sustained by a corresponding increase
in glucose consumption and reduction in pyruvate to lactate
while NADH is oxidized to NADþ. The increased rate of ATP
production has to be matched by a corresponding rate in glu-
cose consumption with expectant hypoglycemia unless an ade-
quate supply of glucose is maintained. A compromised
oxidative phosphorylation also cannot adequately recycle the
vast amount of Hþ that is released when ATP is hydrolyzed for
cellular energetics, and when the endogenous buffering capac-
ity is overwhelmed, metabolic acidosis ensues.
As glycolysis intensifies and the supply of glucose
becomes critical, cellular fuel selection switches from glucose
6 Journal of Intensive Care Medicine XX(X)
to fat (ie, glucose fatty acid or Randle cycle). Triacylglycerols
are mobilized and broken down to fatty acids and glycerol.
Fatty acid b-oxidation produces acetyl-CoA, which can serve
as fuel when processed through the citric acid cycle. How-
ever, b-oxidation and acetyl-CoA entry into the citric acid
cycle are hindered because of limited NADþ. Acetyl-CoA
accumulates and high levels of acetyl-CoA favors the forma-
tion of acetoacetate and a high mitochondrial REDOX state
favors the reduction of acetoacetate to b-hydroxybutyrate.
Glycerol can be phosphorylated to glycerol 3-phosphate and
enters the gluconeogenic pathway at DHAP, but this pathway
is muted with the inhibition of mGPD and prevents the oxida-
tion of glycerol 3-phosphate to DHAP. However, if glycerol
flux becomes significant (eg, lipolysis), its oxidation to
DHAP by cGPD with an increase in cytosolic NADH
becomes favorable; production of DHAP and NADH by
cGPD running in the opposite direction.75 Although this gly-
cerol–gluconeogenic pathway may be possible, it is an unfa-
vorable reaction because it has to occur at the expense of
exacerbating a high cytosolic REDOX state created by the
paralysis of glycerol phosphate and MAL-ASP shuttles. A
high cellular REDOX state limits fatty acid b-oxidation and
its usefulness as a fuel source. Cellular fuel selection turns to
protein. Amino acids (eg, alanine) are released from muscles
as a source of precursors for gluconeogenesis via pyruvate.
However, gluconeogenesis is an energy costly process and
cellular bioenergetics is relying on glycolysis for ATP pro-
duction. Processes that are ATP costly are unfavorable. As
alanine entry into gluconeogenesis is impeded, alanine
accumulates.74,76
The dominant source of metabolic acidosis associated with
hyperlactatemia in metformin toxicity is the rapid cytosolic (ie,
nonmitochondrial) ATP turnover (ie, glycolytic generation of
ATP coupled to ATP hydrolysis) when complex I is inhibited
and oxidative phosphorylation cannot adequately recycle the
vast quantity of Hþ from ATP hydrolysis.65,77-82
Animal model of severe metformin toxicity and human cel-
lular biochemical, metabolic, and hemodynamic data from
metformin and phenformin toxicity suggest the biochemistry
and biochemical pathways involved in lactate metabolism and
mechanisms of hyperlactatemia and metabolic acidosis may be
clinically relevant. Data from a swine model of severe metfor-
min toxicity suggest there is decreased global oxygen con-
sumption and mitochondrial dysfunction in heart, kidney,
liver, skeletal muscle, and platelets. Hyperlactatemia per se
does not decrease whole-body respiration, and diffuse inhibi-
tion of cellular respiration and secondary lactate overproduc-
tion contribute to the observed metabolic acidosis and
hyperlactatemia of metformin toxicity.83 In vitro healthy
human donor platelets studies demonstrate metformin
increased lactate production and glucose consumption and
decreased the activity of oxidative phosphorylation complex
I, mitochondrial membrane potential, and oxygen consumption
in a dose- and time-dependent manner. These changes occurred
independently from hypoxia and differences in platelet count
and mitochondrial density.83 Ex vivo studies of human platelets
harvested within 48 hours of patients diagnosed with hyperlac-
tatemia and metabolic acidosis from metformin toxicity show
significantly lower oxidative phosphorylation complex I and
complex IV activity compared to healthy controls.83 Metabolic
profile from patients with metformin or phenformin toxicity is
characterized by hyperlactatemia, metabolic acidosis, signifi-
cant increase in lactate/pyruvate ratio (eg, 2- to 200-fold), and
blood alanine concentration (eg, 4- to 13-fold).70,72-74,84,85
Hemodynamic studies of metformin or phenformin toxic
patients without cardiac or liver failure or sepsis show severe
hyperlactatemia and metabolic acidosis and abnormally low
systemic oxygen consumption despite normal or increased glo-
bal oxygen delivery.86 Resolution of drug intoxication is par-
alleled by correction of hyperlactatemia and metabolic acidosis
with normalization of systemic oxygen consumption.
Another expected consequence of accelerated glycolysis
and muted gluconeogenesis is cellular hypoglycemia. Data
from in vitro human platelets study suggest that metformin
decreases plasma pH and increases cellular glucose consump-
tion and lactate production in a dose-dependent manner and
that plasma glucose concentrations are inversely correlated
with lactate concentrations. 83 Clinically, there have been
numerous case reports of hypoglycemia associated with met-
formin toxicity, and one case seems particularly relevant in
that severe hypoglycemic episodes appeared proximate to
when hyperlactatemia and metabolic acidosis were most
severe.87
It may be expected that a state of relative or absolute insulin
deficiency (eg, diabetes mellitus), superimposed upon metfor-
min toxicity, may potentiate hyperlactatemia, metabolic acido-
sis, and cellular hypoglycemia. That is, hyperlactatemia,
metabolic acidosis, and cellular hypoglycemia may be more
severe in metformin toxic patients with diabetes mellitus. Insu-
lin deficiency would also aggravate lipolysis and promote mus-
cle breakdown with release of amino acids.
The same mechanisms describing hyperlactatemia, meta-
bolic acidosis, and cellular hypoglycemia in metformin toxicity
apply to phenformin toxicity.66,88-90 However, phenformin
inhibits oxidative phosphorylation complex I more effectively
than metformin. This is probably because phenformin is sig-
nificantly more hydrophobic, allowing it to more readily enter
and accumulate in the mitochondria; positively charged bigua-
nides accumulate in the mitochondria in response to the poten-
tial difference across its inner membrane.67,91
Acute Overdose
Large acute overdoses can lead to significant toxicity and can-
not be explained by any other major risk factor other than a
biguanide overdose.92,93 The toxic dose that leads to hyperlac-
tatemia and metabolic acidosis is unclear, but large doses are
typically reported.94-100 A case series of acute metformin
ingestions over 20 years reported adult ingestions of 3.5 to
22.5 g did not develop hyperlactatemia or metabolic acido-
sis. 101 Lacher described a 15-year-old girl who ingested
38.25 g and developed “lactic acidosis” and moderate renal
Wang and Hoyte
failure.96 There have also been reports of survival after acute
ingestions of 60 to 100 g of metformin and pH as low as
6.38.97-100
The clinical course of acute unintentional pediatric metfor-
min exposures appears to be generally benign. In a review of 55
pediatric patients, age 15 months to 17 years, metformin expo-
sure from 8 regional poison centers reported that assessable
patients did not develop hypoglycemia, metabolic acidosis, or
hyperlactatemia and exposure to metformin 1700 mg did not
lead to acidosis or significant clinical illness.95 However, none
of these exposures were confirmed by metformin concentra-
tions, 62% were not assessed for acidosis, and 31% did not
have serial glucose measurements.
Glucose abnormalities have been reported in acute overdose
settings. Hyperglycemia was reported in an otherwise healthy
young patient who ingested over 60 g of metformin and devel-
oped renal insufficiency and severe “lactic acidosis.”102 A
review of all metformin exposures reported to a regional poison
center found 1.5% of patients developed hypoglycemia.103
Hypoglycemia was described in a 15-year-old girl who
ingested 75 g of metformin and 3 g of quetiapine, who devel-
oped “lactic acidosis,” hypotension, and severe hypoglyce-
mia.87 In the setting of hypoglycemia, the clinician should
also remain vigilant for other etiologies of hypoglycemia or
other exposures, as many patients taking metformin also take
sulfonylureas or insulin.
Adverse Events in Therapeutic Setting
Hyperlactatemia and metabolic acidosis are very rare during
therapeutic metformin dosing in patients without comorbid-
ities. In an animal model, rats were fed 1, 200, 600, 900, or
1200 mg/kg/d for 13 weeks. Doses >600 mg/kg/d were associ-
ated with minimal metabolic acidosis characterized by
increased serum lactate and b-hydroxybutyrate concentrations;
however, doses >900 mg/kg/d were associated with some ani-
mals being moribund. The no-observable-adverse-effect level
was 200 mg/kg/d, which corresponds to approximately twice
the plasma metformin concentration and 8 times the maximum
plasma concentration achieved in humans following a 2000 mg
total daily dose.104
Within the first 13 months of metformin approval in the
United States, 47 patients on metformin therapy with con-
firmed “lactic acidosis” (lactate >5 mmol/L) were reported to
the FDA.105 Of these 47 patients, 43 had at least one risk factor
(eg, cardiac disease, renal insufficiency, pulmonary disease,
and older age) for “lactic acidosis” and 20 of these patients
died.106 Only 4 patients had no apparent risk factors and they
all recovered.105 Based on an estimate of 1 million Americans
were taking metformin during this time, the reported rate of
confirmed “lactic acidosis” is about 5 cases per 100 000
(47/1 000 000), which suggests the overall development of
hyperlactatemia and metabolic acidosis in patients on metfor-
min therapy to be very rare. This also suggests development of
hyperlactatemia and metabolic acidosis in patients without
risk factors is 0.4 in 100 000 (4/1 000 000) compared to
7
4.3 in 100 000 (43/1 000 000) in patients with risk factors or
comorbidities.105
Patients who develop hyperlactatemia and metabolic acido-
sis while on metformin therapy are often categorized into 2
different types of toxicity: the so-called metformin-associated
lactic acidosis (MALA) and metformin-induced lactic acidosis
(MILA). These terms are sometimes used interchangeably and
poorly defined. For the purposes of this review, MALA occurs
in the setting of a patient receiving therapeutic metformin and
develops severe pathology but does not have significant met-
formin accumulation. Common comorbidities include shock
states (eg, distributive, hypovolemic, and cardiogenic),
obstructive pulmonary disease, heart failure, respiratory fail-
ure, and hepatic failure.105-109 In this setting, an etiology cannot
be directly or solely attributed to metformin and is usually
associated with other coexisting states. The MILA is also in
the setting of therapeutic metformin, but metformin accumula-
tion has some degree of responsibility. This is of greatest con-
cern in patients with renal insufficiency whose metformin
dosing has not been accordingly adjusted.21,110-112 Since met-
formin is almost entirely eliminated by the kidneys, renal
impairment is a major risk factor for development of MILA.
Acute kidney injury leads to decreased metformin elimination
and increased metformin systemic concentrations during ther-
apeutic dosing. Cimetidine reduces metformin tubular secre-
tion, but is unclear how much this contributes to toxicity.2
Besides hyperlactatemia and metabolic acidosis, there
have also been rare reports of metformin toxicity leading to
encephalopathy, hyperglycemia, hypoglycemia, and pancreati-
tis.113-117 In one case series, a patient developed encephalopa-
thy temporally related to metformin therapy that resolved after
its withdrawal, while another patient had been treated with
metformin for years prior to presentation and developed ence-
phalopathy following initiation of repaglinide.113 Interestingly,
this patient became asymptomatic when repaglinide and met-
formin were discontinued, but encephalopathy recurred when
patient was rechallenged with metformin. Others have reported
encephalopathy and parkinsonian symptoms in patients who
received metformin in the setting of end-stage renal disease
requiring dialysis.114-116 Symptoms were correlated with high
signal intensity in the basal ganglia on MRI T2-weight images
that resolved when metformin was discontinued and with clin-
ical improvement.115,116
It is rare for patients on metformin therapy to experience
hypoglycemia. The incidence of moderate to severe hypogly-
cemia for patients on metformin therapy is 60 per 100 000, and
the odds ratio of developing moderate to severe hypoglycemia
associated with metformin use is 1.42 (95% confidence inter-
val: 1.22-1.64).117
Diagnosis of Metformin Toxicity
History and physical examination are mainstays in diagnosing
metformin toxicity. Of course, history of acute overdose should
lead to appropriate evaluation. However, signs and symptoms
of metformin toxicity in the therapeutic setting can be
8 Journal of Intensive Care Medicine XX(X)

nonspecific and pose a diagnostic challenge.111,112 Signs and Table 1. Differential Diagnosis for Hyperlactatemia and Associated
symptoms include nausea, vomiting, fatigue, hypovolemia, Metabolic Acidosis.
altered mentation, poor urine output, tachycardia, tachypnea, Toxicological Etiology Nontoxicological Etiology
and hypotension or shock.
Serum biguanide concentrations in the acute overdose set- Cyanide Sepsis
ting are unhelpful in patient management. Serum metformin Hydrogen sulfide Shock
concentration may aid in determining the final diagnosis of Rotenone Status epilepticus
HIV antiretrovirals (nucleoside Inborn error of metabolism
a patient but will unlikely return in a timely fashion and
reverse transcriptase inhibitor)
unlikely affect acute clinical management. Overall, it is rare Isoniazid Antibacterial-induced D-lactic
to have significant metformin accumulation without acidosis
hyperlactatemia and metformin-induced hyperlactatemia with- Linezolid Liver failure
out metformin accumulation.118 Metformin concentrations Propylene glycol Warburg effect
typically associated with hyperlactatemia and metabolic acido- Propofol infusion syndrome
sis are >5 mg/mL.92,119,120 Adrenergic stimulants
(eg, theophylline, salbutamol)
Nalidixic acid
Prognostic Factors Acetaminophen (massive overdose)
Fructose
Acute Overdose
There are case reports of patients who survived acute serious
ketoacidosis, alcoholic ketoacidosis, and xenobiotic-induced
metformin overdoses with serum pH 6.38 and hyperlactatemia
myocardial suppression).
(>20 mmol/L).96-101 However, survival rates appear higher in
patients without profound acidemia and hyperlactatemia. Del-
l’Anglio and colleagues performed a literature review and found Treatment
22 cases of acute metformin overdoses with documented serum
There is no specific antidote for metformin toxicity and its
pH, lactate levels, and metformin concentrations and found no
mainstay of therapy is supportive care, which should include
patient with a nadir serum pH >6.9, lactate concentration
management of fluids, electrolytes, acid–base, respiratory,
<25 mmol/L, or peak serum metformin concentration <50 mg/mL
metabolic, renal, and hemodynamic derangements. Some
died.121 Seidowsky and colleagues reported the overall relative
adjunct therapies to consider include gastrointestinal deconta-
risk for death was higher in metformin overdose patients with a
mination, glucose and insulin, serum alkalinization, extracor-
serum pH 7.2 and arterial lactate 15.122 When compared
poreal techniques to reduce metformin body burden, and
with patients with incidental overdoses, patients with intentional
metabolic rescue. Gastrointestinal decontamination (eg, gastric
overdoses developed less acidosis, developed end-organ dys-
lavage and activated charcoal) should be considered following
function, and had better survival rates.122 Prothrombin time has
a serious acute metformin overdose provided there is no
also been evaluated as a prognostic factor. Prolonged prothrom-
contraindications.
bin time appears to be a good predictor of mortality in patients
with metformin toxicity.122-124
Extracorporeal Techniques
Toxicity in Therapeutic Setting Extracorporeal techniques (eg, hemodialysis, continuous renal
Case series suggest serum lactate, pH, or metformin concen- replacement therapy [CRRT], hemoperfusion, and plasma
tration did not have prognostic value in patients who develop exchange), either alone or in combination, have been used to
toxicity while on therapeutic metformin dosing. Lalau and treat both acute metformin overdoses and metformin toxicity in
Race reported a series of 49 patients who developed “lactic the therapeutic setting.128-145
acidosis” while on metformin therapy and found there was no If hemodialysis can be tolerated, it can reduce metformin
difference in median arterial lactate level between patients who body burden, clear lactate, and correct acid–base abnormalities
survived and died, and plasma metformin concentrations were with great efficiency. However, seriously ill patients often have
3 times higher in patients who survived.125 Several other stud- marginal hemodynamics or are hemodynamically unstable and
ies have reported similar lack of predictive value of arterial pH, may not tolerate standard hemodialysis measures. The different
serum metformin, and arterial lactate concentrations.120,126,127 CRRT modalities (eg, continuous veno-venous hemofiltration,
continuous veno-venous hemodialysis, and continuous veno-
venous hemodiafiltration) may be reasonable alternatives to
Differential Diagnosis hemodialysis, as they cause less adverse hemodynamic effects
Differential diagnosis of metformin toxicity (Table 1) than with hemodialysis. However, CRRT is intended to substi-
includes toxicological and nontoxicological etiologies of tute for impaired renal function over an extended period and
hyperlactatemia and metabolic acidosis.83,86 Additional con- applied for 24 hours a day. Continuous renal replacement ther-
siderations include severe systemic illnesses (eg, diabetic apy is not intended to and cannot substitute for hemodialysis as
Wang and Hoyte
a method to achieve rapid xenobiotic (eg, metformin) clearance
compared to other modalities. Metformin has a low molecular
weight and low protein binding and is freely soluble in water,
making it amenable to plasma clearance by CRRT. However,
metformin has a relatively high volume of distribution
(3.1 L/kg) and it has been estimated it takes an average of
15 cumulative hours of intermittent hemodialysis to achieve
therapeutic metformin concentrations following an overdose,
and the maximum metformin clearance rate has been reported
to approach 2.4%/h during CRRT.122,134,137,140,141
Alkalinization
The benefit of base therapy in the treatment of metabolic acido-
sis associated with metformin toxicity is unclear. Base therapy
for metabolic acidosis is recommended at an arterial pH vary-
ing from 6.9 to 7.2.146 It is reasonable to consider base therapy
when arterial pH is less than 7.20 in the presence of underlying
cardiovascular disease or evidence of hemodynamic compro-
mise, as lower values may impair cardiovascular function and
is associated with increased mortality.147-150 Unless efforts are
directed at reversing the underlying causes for the acidosis,
base therapy is futile. In acidemic states where cardiac output
is inadequate to meet systemic oxygen requirements and is
unimproved by catecholamines, partial correction of arterial
pH may be necessary in order to restore adequate hemody-
namics. The goal is to improve cardiac contractility and restore
responsiveness of the myocardium and peripheral vessels to
endogenous and infused catecholamines, not an arbitrary arter-
ial pH per se. In clinical practice, when base is given, the aim is
to maintain pH *7.2.151-153
Sodium bicarbonate is the most commonly used base. Man-
agement of “lactic acidosis” with the use of sodium bicarbonate
is controversial despite its regular use. The source of metabolic
acidosis and lactate during metformin toxicity is intracellular.
An increase in serum lactate concentration occurs when lactate
diffuses out of cells and enters the extracellular compartment.
Thus, the primary problem is not in the extracellular compart-
ment and administration of sodium bicarbonate does not
directly address the intracellular problem. Extracellular hydro-
gen and bicarbonate ions do not readily diffuse across cell
membranes into the intracellular compartment where the pur-
ported benefits of bicarbonate therapy occur. Administered
bicarbonate reacts with acids to form water and carbon dioxide,
which readily diffuses into the intracellular compartment and
drives the formation of hydrogen and bicarbonate ions; sodium
bicarbonate administration will cause intracellular acidosis
unless the partial pressure of carbon dioxide can be decreased
by increased ventilation. Thus, sodium bicarbonate administra-
tion, which increases extracellular pH, would not be expected
to readily correct intracellular acidosis and improve hemody-
namics or augment sensitivity to catecholamines.154 Most
patients treated with conventional doses of bicarbonate showed
no increase in cardiac output or decrease in morbidity or mor-
tality.155 However, those treated with large doses of bicarbo-
nate and concomitant dialysis appeared to have a decrease in
9
mortality. This suggests administration of large quantities of
bicarbonate may prolong survival to allow treatment of the
underlying cause of “lactic acidosis.”156 In terms of biguanide
toxicity, a retrospective review of more than 300 cases of
biguanide metabolic acidosis and hyperlactatemia, survival of
patients who were administered bicarbonate was no better than
patients who received supportive care.60 Given the limited
options when metabolic derangement result in a pH less than
7.20 in the presence of underlying cardiovascular disease or
evidence of hemodynamic compromise, it is reasonable to con-
sider sodium bicarbonate as a pH buffer while awaiting the
deployment of hemodialysis. Sodium bicarbonate may deliver
an unwanted sodium load to patients with marginal cardiac
reserve and may contribute to adverse cardiovascular events.
Tris-hydroxymethyl aminomethane (THAM) is an alterna-
tive alkalinizing agent to sodium bicarbonate. In contrast to
sodium bicarbonate, THAM is a proton acceptor by virtue of
its amine group and neutralizes acids without generating car-
bon dioxide. Tris-hydroxymethyl aminomethane readily dif-
fuses through the extracellular space and moves into the
intracellular compartment. Thus, THAM is able to balance
pH in the setting of acidemia due to metabolic acid accumula-
tion or carbon dioxide retention. It is excreted in its protonated
form at a rate exceeding creatinine clearance and thus it may be
less effective in renal dysfunction. However, THAM is dialyz-
able and renal dysfunction does not obviate its use. Tris-
hydroxymethyl aminomethane may lower the partial pressure
of carbon dioxide as effectively as sodium bicarbonate and
improves cardiac contractility in parallel with improvement
in acid–base balance. 157-159 Tris-hydroxymethyl amino-
methane has been used in conjunction with renal replacement
therapy in an acute overdose of metformin.160
Glucose and Insulin
Hypoglycemia should be aggressively treated with intravenous
dextrose. Glucose and insulin therapy is reasonable as it pro-
vides a source of glucose, facilitates glucose utilization, sus-
tains glycolysis, mitigates hypoglycemia, and attenuates
lipolysis. The benefit of glucose and insulin therapy is sug-
gested by clinical experience with their use in severe phenfor-
min toxicity in which mortality appears to be significantly
reduced compared with patients who were not treated with
glucose and insulin.4
Metabolic Rescue
Methylene blue (MB) may be considered as a metabolic rescue
for metformin toxicity. Treatment that could help bypass elec-
tron transport impediment at complex I and support electron
transport, mitochondrial membrane potential, and ATP produc-
tion may be helpful. Methylene blue can serve as an alternative
electron carrier by accepting electrons from NADH and is
reduced to leucomethylene blue, which can then deliver its
electrons to either ubiquinone or cytochrome c, thus resuscitat-
ing oxidative phosphorylation and the citric acid cycle and in
10
the process regenerating MB.161-164 Although this may be
mechanistically reasonable, the effectiveness of MB as an
adjunct treatment is unclear. However, there are at least 5 case
reports of serious metformin toxicity in which MB was used as
adjunct therapy with 80% survival.165-169 Methylene blue may
also address other pathophysiologic effects. Some evidence has
shown metformin increases peripheral perfusion via activation
of endothelial nitric oxide synthase (eNOS).170 Perhaps, MB
may improve responsiveness to vasopressors, in addition to
attenuating metformin’s activation of the eNOS system.
Conclusion
Biguanides include various medications, disinfectants, and
experimental compounds based on the biguanidine molecule.
Currently, the most commonly used biguanides is the antidia-
betic pharmaceutical metformin. Adverse effects include gas-
trointestinal upset, vitamin B12 deficiency, and hemolytic
anemia. Severe metformin toxicity characterized by hyperlac-
tatemia and metabolic acidosis occurs during therapeutic dos-
ing in the setting of coexisting conditions such as renal failure
and following acute serious overdose. Although hyperlactate-
mia and metabolic acidosis are markers of metformin toxicity,
the degree of hyperlactatemia and severity of acidemia have
not been shown to be of prognostic value. Regardless of the
etiology of toxicity, treatment should include supportive care
and consideration for adjunct therapies such as gastrointestinal
decontamination, glucose and insulin, alkalinization, extracor-
poreal techniques to reduce metformin body burden, and meta-
bolic rescue.
Acknowledgments
The authors would like to acknowledge Dr Luke Yip for his significant
contributions to the pathophysiology section and discussion of methy-
lene blue as a metabolic rescue agent.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
George Sam Wang, MD http://orcid.org/0000-0002-2931-3508
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