Metformin, an antihyperglycemic, is widely used in the treatment of type 2 diabetes mellitus (DM). A rare, but important
complication associated with this drug is the development of lactic acidosis: Overall mortality of lactic acidosis is approximately
50%. Certain subsets of patients taking metformin are at greater risk of developing lactic acidosis. This report discusses
the development of metformin-associated lactic acidosis in four older adults admitted to an institution during a 2-month period,
treatments, and outcomes. We recommend an aggressive treatment strategy of hemodialysis followed by peritoneal dialysis, continuous
bicarbonate infusion, and tight glucose control. We review the cautions and contraindications of metformin use for the treatment
of type 2 DM and report an educational plan for residents and staff instituted to improve drug complication awareness and
reduce mortality.
DePalo VA, Mailer K, Yoburn D, Crausman RS. Lactic acidosis associated with metformin use in the treatment of type 2 diabetes
mellitus. Geriatrics 2005 60(Nov):36-41.
Key words: metformin • type 2 diabetes mellitus • lactic acidosis
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Metformin, a dimethylbiguanide,is an oral antihyperglycemic medication used to treat type 2 (non-insulin-dependent) diabetes
mellitus. Metabolic abnormalities associated with type 2 diabetes result from impaired insulin secretion and insulin resistance.1 Until 1995, when metformin was approved for use in the United States, sulfonylureas were the only oral medications for type
2 diabetes available since the 1970s, when phenformin was taken off the market.2 Sulfonylureas improve insulin secretion.3 Biguanides induce anorexia, decrease carbohydrate absorption, inhibit gluconeogenesis, and increase cellular uptake of glucose.4 Metformin improves insulin sensitivity and decreases insulin resistance.5-7 It is one of the most widely prescribed medications for type 2 diabetes.
Phenformin, introduced in 1957, was withdrawn from the market because of the development of lactic acidosis.4 Metformin is a congener of phenformin with a lesser tendency for causing lactic acidosis.7 But in a subset of patients, the risk of lactic acidosis remains important. Renal dysfunction, cardiac failure, chronic
hepatic dysfunction, and significant chronic pulmonary disease are among the contraindications to treatment with metformin.8,9 The overall mortality is estimated to be approximately 50%.4,10
Table Cautions/contraindications to metformin use in case patients
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We report on four older adults admitted to our institution during a 2-month period, who developed lactic acidosis in the setting
of type 2 diabetes therapy with metformin, their treatments, and outcomes.
Patient 1
An 85-year-old woman was admitted with malaise and dehydration. She had a creatinine level of 2.2 mg/dL, and a digoxin level
of 2.5 mg/dL. The anion gap was 16 and HCO3 was 22 mmol/L. Chest radiograph showed findings consistent with congestive heart failure.
Her medical problems included type 2 diabetes, diabetic retinopathy, chronic renal disease, chronic atrial fibrillation, a
prior MI, and anemia. Her medications included furosemide, hydroxyzine hydrochloride, amlodipine, warfarin, enalapril, metformin,
and digoxin.
On the 7th hospital day, the anion gap was 18, arterial pH was 7.25, HCO3 was 13 mmol/L, lactate was 8.8 mmol/L, and creatinine was 2.0 mg/dL. Metformin was discontinued when it was determined that
the patient had a metabolic acidosis. The patient was treated with intermittent intravenous sodium bicarbonate and a total
of 32 hourly peritoneal dialysis (PD) sessions. She refused hemodialysis and other treatments. The patient ruled in for an
MI. On the 9th day, the patient had a cardiac arrest.
Patient 2
A 72-year-old woman presented with increased shortness of breath and abdominal discomfort that lasted for 1 week. She was
hypotensive, requiring volume resuscitation and vasoactive medications, she was admitted with hypotension, metabolic acidosis
(HCO3, 18 mmol/L, pH 7.17, anion gap 16), and presumed infection. Chest radiograph showed hyperinflated lungs consistent with chronic
obstructive pulmonary disease (COPD). Hemoglobin decreased from 11.2 gm/dL to 6.0 gm/dL over a one-month period, due to a
GI bleed.
Medical history included hypertension, type 2 diabetes, prior MI, pulmonary embolism, cerebral vascular accident (CVA), and
severe COPD (FEV1 , 500 ccs). Medications included verapamil, enalapril, furosemide, prednisone, tolbutamide, metformin, warfarin, albuterol
and ipratropium bromide, and terfenadine.
Metformin was stopped on admission. The patient was started on antibiotics and methylprednisolone for a COPD exacerbation.
The patient's lactate level was 7.8 mmol/L, creatinine level was 2.1 mg/dL, and glucose was 340 mg/dL. Her treatment included
blood transfusion, a 3-hour session of hemodialysis, 29 PD sessions, and a bicarbonate infusion. Her respiratory system was
unable to compensate for the acid-base derangement. The patient did not want endotracheal intubation, so non-invasive positive
pressure mechanical ventilation (NPPV) was initiated. Glucose was difficult to control, she required a continuous insulin
infusion.
On the 4th day, acid-base status and glucose level had improved. PD and the bicarbonate and insulin infusions were discontinued.
Although the lactic acidosis cleared with treatment (lactate level 1.7 mmol/L, anion gap 2, and pH 7.33), the renal failure
worsened. She continued on NPPV. On the 7th day, she became hypotensive and died. The lactic acid level was 1.8 mmol/L; the
creatinine level was 2.6 mg/dL; the anion gap was 9.
Patient 3
An 80-year-old man was admitted with fever, cough, and weakness. He was tachypneic, oxyhemoglobin saturation was 89% to 90%,
and breath sounds were decreased at the right lung base. Chest radiograph confirmed a right lower lobe infiltrate.
Medical history included type 2 diabetes, MI, femoral-popliteal bypass graft, emphysema, and pulmonary fibrosis not requiring
corticosteroids or supplemental oxygen. His medications included metformin, enalapril, sertraline hydrochloride, and glipizide.
Metformin was discontinued on admission. The patient was started on ciprofloxacin, methylprednisolone, ipratropium bromide
and albuterol, and oxygen. The pH, anion gap, and HCO3 were 7.28, 16, and 16 mmol/L, respectively. Lactic acid level was 6.0 mmol/L. Treatment with hemodialysis, PD, and a bicarbonate
infusion was started. Liver function tests were normal. After one 3.5-hour session of hemodialysis and 49 hourly PD sessions,
the pH was 7.44, anion gap was 5, HCO3 was 27 mmol/L, and lactate was 1.7 mmol/L by the 4th day. PD and the bicarbonate infusion were discontinued. The pneumonia
improved and the patient was discharged home on the 10th day.
Patient 4
A 72-year-old man maintained on home oxygen for pulmonary fibrosis presented with acute shortness of breath and weakness.
Breathing improved after treatment with albuterol. The patient was admitted for digoxin toxicity (3.0 mg/dL).
Medical history included type 2 diabetes, chronic renal disease, prior MI, prior CVA, pulmonary fibrosis, and obstructive
sleep apnea. Medications included furosemide, digoxin, isosorbide dinitrate, metformin, glyburide, captopril, ipratropium
bromide, albuterol, and prednisone.
On admission, HCO3 was 18 mmol/L, pH was 7.37, anion gap was 16, creatinine level was 2.5 mg/dL, and glucose was 605 mg/dL. Metformin was discontinued.
An insulin infusion was started. Serum ketones were negative and the lactate level was 5.9 mmol/L. Liver function tests were
normal. A bicarbonate infusion, hemodialysis, and PD were started. On the 6th day, treatment for lactic acidosis was discontinued
(anion gap 12, HCO3 , 31 mmol/L, and lactate 3.0 mmol/L). The creatinine level was 1.4 mg/dL and glucose was 211 mg/dL. The patient received
one 3.5-hour hemodialysis session and 67 hourly PD exchanges for a fluctuating lactate level. The patient was discharged home
on the 11th day.
Lactic acidosis
Lactic acidosis causes an anion gap metabolic acidosis with a blood lactate level ≥ 5 mmol/L. Lactate accumulation results
from increased production or decreased metabolism and excretion. Biguanides interfere with production and clearance of lactate.
These drugs can cause a shift in the intracellular redox potential to anaerobic metabolism increasing cellular lactate production.11
Various studies have outlined numerous cautions and contraindications to treatment with metformin.8,9,12,13 Impaired cardiac performance, reduced tissue perfusion, and arterial hypoxemia can result in tissue hypoxia and lactic acid
production.4 An increase in lactic acid can also occur with diabetes mellitus (type 1 or type 2), certain malignancies, and congenital
diseases of the liver.
Cardiac failure, demonstrated by catheterization or echocardiography or defined as chronic treatment with diuretics, an angiotensin-converting
enzyme (ACE) inhibitor, or both increases the risk of tissue hypoxia. A possible synergistic effect of metformin and enalapril
leading to development of lactic acidosis has been suggested.14 However, this may be due to the widespread use of enalapril for the treatment of cardiac failure.
Coronary heart disease, peripheral vascular disease, and chronic pulmonary disease also increase the risk of tissue hypoxia. Coronary heart disease
has been defined by a positive stress test or angiogram, a previous MI, the presence of bypass surgery, or chronic antianginal
therapy.8 Diabetic patients often have chronic vascular changes that lead to clinically significant vascular disease.
Chronic pulmonary disease can lead to hypoxemia and tissue hypoxia.5,8 In addition, it has been postulated that in acute lung injury, the lung can be an important source of lactate.15
Renal impairment. Metformin is excreted unchanged by the kidney.13 With renal impairment, defined as a plasma creatinine of >1.5 mg/dL in men and >1.4 mg/dL in women, there is a diminished
clearance of metformin. Lactate is metabolized in the liver and cleared by the kidneys. Chronic hepatic or renal dysfunction
can lead to increased lactate levels.
Other risk factors. Other important risk factors include:
- Age
- alcohol intake
- diabetic retinopathy
- diabetic ketoacidosis or other acidotic conditions
- use of intravenous contrast because of the risk of acute tubular necrosis
- high daily doses of metformin
- B12 , folate, or iron deficiency.8
Discussion
Controversy exists over the link between metformin use and lactic acidosis.16 Is metformin the cause of or coincident to the development of lactic acidosis? A study of pooled data from 194 studies revealed
no evidence of fatal or nonfatal lactic acidosis and a Cochrane Systematic Review concluded that there was no increased risk
of lactic acidosis with metformin treatment.17,18 In a case report review of patients taking metformin who developed lactic acidosis, Staedes et al19 reported that 46 of 47 cases had at least one risk factor for the development of lactic acidosis, but 1 case had no identifiable
risk factor.
We described lactic acidosis of multifactorial etiology in four older adults, and their outcomes. All were taking metformin
and had multiple risk factors for the development of lactic acidosis (table). Metformin was stopped on admission in three
patients and discontinued on day seven in one patient when metabolic acidosis was recognized. Two patients had acute processes
(pneumonia, sepsis) that could contribute to lactic acidosis development.
Although three patients had underlying chronic pulmonary disease, only one (with pneumonia and pulmonary fibrosis) had documented
hypoxemia. All three were treated with high-dose corticosteroids. Corticosteroid drugs may act as an additional risk factor
contributing to the development of lactic acidosis through a catabolic effect.
Three patients were aggressively treated with hemodialysis, hourly PD, and a bicarbonate infusion. The bicarbonate, lactate,
and arterial blood pH levels were followed closely. Hemodialysis has been shown to lower plasma metformin levels, however,
a rebound in levels?presumably due to a potentially long half-life (24 hours) and large distribution volume?has been described.20-23 In our patients, there was a rapid decrease in lactate level, which then increased. Hourly PD was instituted. Lactate levels
were reduced despite infusing 40 mmols of lactate with each PD session. We hypothesize that metformin, a small, non-plasma
protein-bound molecule, was dialyzed out of the body with subsequent PD sessions.
The decision to terminate treatment was based on persistently low lactate levels (≤ 3 mmol/L) for a perod of 48 hours. Conditions
that generate lactic acid may lead to level fluctuations as were observed in Patient 4. Uncontrolled hyperglycemia may consequently
drive lactate levels. While lactic acidosis with PD is uncommon, it may lead to above normal lactate levels over time as the
dialysis gradient changes with the removal of lactate.
Two of the three aggressively treated patients survived. In the patient who died, the lactic acidosis had resolved by the
4th day. Her death on the 7th day was related to the inability of her pulmonary function to meet systemic needs, her decision
to decline endotracheal intubation and other treatments, and consequent hemodynamic instability.
We recommend an aggressive treatment strategy for metformin-associated lactic acidosis and further suggest aggressive glucose
control with a low threshold for the institution of a continuous insulin infusion and frequent glucose monitoring.
We saw an increased incidence of lactic acidosis in patients being treated with metformin over a 2-month period. Literature
documents a very low incidence, approximately 0.03 cases per 1,000 patient-years.23 A population study of Saskatchewan residents taking metformin documented 9 cases/100,000 person-yr of metformin exposure.24 Our patients had multiple risk factors that have been reported as cautions and contraindications to metformin treatment
for type 2 diabetes. Some had acute processes and possibly treatments that could lead to lactic acid production.
Based on our experiences, extensive educational review on the cautions and contraindications of metformin was instituted for
the hospital medical and residency staffs. The pharmacy staff was involved in the process by sending an information sheet
to the hospital chart of each patient for whom metformin was ordered. The metformin information sheet also was sent to the
medical directors of area nursing homes.
Many factors can contribute to the development of lactic acidosis. Metformin is an important drug for the treatment of diabetes.
It treats the macrovascular effects of diabetes and there is no additional weight gain as seen with other therapies.25 A recent study of reduced mortality rate in patients with heart failure treated with metformin questions the inclusion of
congested heart failure on the list of cautions and contraindications.26 It may be important to avoid the use of metformin in patients with multiple risk factors for the development of lactic acidosis,
but when it must be used, monitor organ systems for signs of flux in function. Education and recognition of cautions and contraindications
are key to reducing morbidity and mortality.
Dr. DePalo is associate professor of medicine; director, intensive care unit, division of pulmonary and critical care medicine, Brown
Medical School/Memorial Hospital of Rhode Island.
Dr. Mailer is completing fellowship training in geriatrics, Metro Health Medical Center, Case Western Reserve University School of Medicine,
Cleveland, OH.
Dr. Yoburn is clinical associate professor of medicine; chief, division of nephrology, Brown Medical School/Memorial Hospital of Rhode
Island.
Dr. Crausman is assistant professor of medicine; director, internal medicine residency program; chief, division of geriatrics, Brown Medical
School/Memorial Hospital of Rhode Island.
Disclosure: The authors report no relevant financial relationships.
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