Presentation
S.S. was a 53-year-old woman with a history of type 2 diabetes and asthma who presented
to the emergency department with coughing and shortness of breath. Five days before
this visit, she developed wheezing and a cough productive of yellow sputum. Her primary
care physician started her on amoxicillin for possible bacterial bronchitis, but her
symptoms persisted. Three days later, she became acutely short of breath and presented
to the emergency department. At that time, a chest X-ray was obtained, revealing a
linear opacity questionable for pneumonia. She was treated with a nebulizer in the
emergency department, started on prednisone 60 mg for 5 days, and switched from amoxicillin
to levofloxacin. However, despite these interventions, she continued to cough and
experience dyspnea, prompting her return to the emergency department.
At this visit, S.S. denied any fever, chills, anorexia, chest pain, nausea, vomiting,
or diarrhea. Her presenting vital signs included a temperature of 97.7°F, pulse of
118 bpm, blood pressure of 149/91 mmHg, respiratory rate of 24 breaths per minute,
and O2 saturation of 100% on room air. On physical examination, she had end-expiratory
wheezes in the lower posterior lung fields. Her heart was tachycardic without any
murmurs, rubs, or gallops. Otherwise, the physical examination was unremarkable. Initial
chemistry values included sodium of 129 mEq/L, potassium of 4.9 mEq/L, chloride of
93 mmol/L, bicarbonate of 18 mmol/L, glucose of 207 mg/dL, blood urea nitrogen of
32 mg/dL, and creatinine of 1 mg/dL. The serum anion gap was 18. Initial complete
blood count included a white count of 12.0, a hematocrit of 40.0, and a platelet count
of 358,000.
S.S.’s diabetes medication consisted only of metformin, which had been increased 6
weeks earlier to 1,000 mg twice daily. In addition to type 2 diabetes, she had a history
of hypothyroidism, hypertension, asthma, and hyperlipidemia, for which she took levothyroxine,
spironolactone, montelukast, and pravastatin, respectively. She had no history of
acute or chronic renal disease.
In the emergency department, S.S. was given 200 mg of benzonatate orally for her cough
and 1 hour of continuous nebulizer treatment containing albuterol and ipratropium
bromide. However, because her spasmodic coughing did not improve and she denied feeling
better, she was given 125 mg of methylprednisolone and was admitted for observation
and nebulizer treatments. Her antibiotic coverage was also switched to ceftriaxone
2 g intravenously daily and azithromycin 500 mg intravenously daily.
On day 1 of admission, the hospitalist took a detailed medical history and noted that
the patient’s voice was hoarse. S.S. reported that hoarseness had been her most worrisome
and awkward symptom for the past few days and that most of her documented “wheezes”
could be better described as voice hoarseness. On physical examination, her lungs
were clear in all fields, with no prolonged expiration. However, a laryngeal wheeze
was noted. On review of her blood work, the hospitalist reasoned that her low bicarbonate
and normal oxygenation contradicted the diagnosis of asthma exacerbation with pneumonia.
S.S., hoping to find an answer to her persistent unexplainable symptom, agreed to
an arterial blood gas, which revealed metabolic acidosis with secondary respiratory
alkalosis, with a pH of 7.44, PaCO2 of 22 mmHg, PaO2 of 118 mmHg, bicarbonate of 14.9
mEq/L, and oxygen saturation of 99%. The acetone level came back negative, but the
lactate level was found to be increased, at 7.3 mmol/L.
Lactic acidosis secondary to metformin use was suspected, so metformin was discontinued.
Over the next 48 hours, S.S.’s lactate level gradually decreased from 7.3 to 6.5,
5.4, and finally to 3.0 mmol/L, concomitant with an increase in her bicarbonate level
from 16 to 21, and finally to 23 mmol/L. She showed gradual clinical improvement and
remained hemodynamically stable. Her diabetes treatment was changed to detemir 5 units
daily during her hospital stay, but she was switched to glargine on discharge for
better 24-hour coverage. She was not re-challenged on metformin because of the dramatic
response of her lactate level correlating with her improved condition after metformin
was stopped.
Questions
For which patients with diabetes is metformin currently recommended?
Is it possible for a patient with normal renal function to develop metformin-associated
lactic acidosis?
How can health care providers recognize lactic acidosis as a potential complication
of metformin?
Commentary
Metformin is a biguanide that works by increasing insulin-mediated glucose utilization.
In the absence of any contraindications, metformin is considered to be the first-line
pharmacological treatment for type 2 diabetes and should be initiated at the time
of diagnosis, along with lifestyle interventions (1). Some of the advantages of metformin
over other oral antidiabetic medications include a decreased likelihood of hypoglycemia,
favorable effects on lipids, and a decreased likelihood of cardiovascular events and
mortality (2,3). Of all the contraindications to metformin use, impaired renal function
is the most concerning because of the increased risk of lactic acidosis.
Although lactic acidosis is a widely recognized side effect of metformin, its occurrence
is actually quite rare, with an incidence rate of 9 cases per 100,000 person-years
of metformin exposure (4). Most cases of metformin-associated lactic acidosis are
from patients who either had abnormal kidney function or overdosed on metformin. This
case shows a rare instance of metformin-associated lactic acidosis in a patient with
normal renal function taking a normal dose of metformin. A similar case was published
in 2011 by van Stolen et al. (5). In their case, the patient’s serum lactate levels
corresponded to metformin levels at baseline, withdrawal, re-challenge, and subsequent
withdrawal.
It is unclear how frequently these types of responses occur. However, because metformin
is so widely prescribed, it is likely that some other patients taking metformin may
also have increased lactate levels. For this reason, it is important that clinicians
be able to recognize and diagnose metformin-associated lactic acidosis.
Signs and symptoms of lactic acidosis are nonspecific and may include nausea, vomiting,
abdominal pain, anorexia, hyperventilation, or hypotension. Therefore, it is important
to maintain a high index of suspicion for lactic acidosis in patients treated with
metformin. If lactic acidosis is suspected, a basic chemistry workup, an arterial
blood gas, and a lactate level should be ordered. In this case, we suspect that concomitant
acute illness such as pneumonia may have played a role in the development of lactic
acidosis in this patient with diabetes and normal kidney function.
Clinical Pearls
Metformin-associated lactic acidosis remains a rare complication of a common medication.
Metformin-associated lactic acidosis should not be automatically excluded in patients
with normal renal function, particularly in the presence of a concomitant acute illness.
Health care providers should consider ordering a serum lactate level for acutely ill
patients taking metformin, especially in the presence of acidosis on blood chemistry
results.