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Author: Allegra J.

Melillo, MD 4/10/2003
Reviewer: David Thom, MD, PhD

Metformin Should Be Used Cautiously In


Hospitalized Patients
Question:
• Many providers discontinue prescribing metformin to patients with type II
diabetes who are hospitalized because of the concern that patients may develop
one of the risk factors associated with metformin associated lactic acidosis
(MALA). Is there evidence that patients with type II diabetes who are admitted
to the hospital without existing contraindications to metformin have an increased
risk to develop lactic acidosis while on Metformin compared to other non-
biguanide therapies?

Clinical Bottom Lines


• There are no clinical trials that specifically examine the question.
• In patient populations without contraindications, metformin has not been found to
be associated with an increased risk of lactic acidosis or with increased levels of
lactate compared to other anti- hyperglycemic treatments.
• However, if metformin is not routinely discontinued for all admissions, there may
be an increased risk of it being continued despite contraindications present at the
time of admission or that develop during hospitalization.
• Therefore, providers must use caution if they are to continue patients on
metformin during a hospitalization and be aware of the current contraindications
of treatment.

Evidence
• In the Cochrane systematic review, pooled data from 176 comparative trials and
cohort studies (taking account contraindications) revealed no cases of fatal or
nonfatal lactic acidosis in 35,619 patient- years of metformin use or in 30,002
patient-years in the non-metformin group. (1)
• Using Poisson statistics with 95% confidence intervals the upper limit for the true
incidence of metformin-associated lactic acidosis was 8.4 cases per 100,000
patient-years and the upper limit for the true incidence of lactic acidosis in the
non- metformin group was 9 cases per 100,000 patient-years. (1)
• The University of Pittsburgh Medical Center Presbyterian (UPMC) conducted a
case-control study of 263 hospitalizations involving 204 patients who received at
least 1 dose of metformin during inpatient admission. In this study patients in 71
admissions (27%) had at least 1 absolute contraindication to metformin at the time
of or during the time of admission. In 29 (41%) of these 71 admissions, treatment
with metformin continued despite the contraindication. (2)
• The most common contraindication, elevated serum creatinine concentration, was
present or developed during 32 admissions (12%); however, metformin use was
discontinued in only 8 of these 32 patients. (2)

1
Comments
• The Cochrane review is the most comprehensive and rigorous study examining
the potential increased risk of lactic acidosis from metformin. However, the
authors were not able to quantitatively assess the safety of metformin treatment in
the presence of each of hypoxic conditions (see table below for contraindications)
because the data excluded most contraindications and those patients with
contraindications such as renal or hepatic insufficiency who were included were
not separated into subgroups.
• The UPMC trial was only focused on whether prescribers were complying with
the labeled contraindications and precautions to the use of metformin instead of
verifying that metformin therapy causes lactic acidosis in patients at increased
risk.

Absolute Contraindications Precautionary Contraindications


• Renal disease or renal dysfunction • Age >= 80 y, unless measurement of
(specifically Cr >=1.5 mg/ml in creatinine clearance demonstrates that
males and >=1.4 mg/ml in females renal function is not reduced
• Congestive heart failure requiring • Clinical or laboratory evidence of hepatic
pharmacological treatment disease
• Acute or chronic metabolic • Concomitant cationic drug use (e.g.
acidosis Vancomycin)
• Metformin use should be • Presence of any condition associated with
discontinued at the time of a hypoxemia (eg, COPD and acute MI),
procedure requiring intravascular dehydration, or sepsis
iodinated contrast material, for at • Excessive alcohol intake
least 48 h after the procedure, and • After any surgery until patient’s oral
until renal function is deemed intake is resumed and renal function is
normal. deemed normal.

Citations
Salpeter S, Greber E, Pasternak G, Salpeter EA. Risk of fatal and nonfatal lactic acidosis
with metformin use in type 2 diabetes mellitus (Cochrane Review). In: The Cochrane
Library, Issue 1, 2003. Oxford Update Software.

Calabrese A, Coley K, DaPos S, Swanson D. Evaluation of prescribing practices: risk of


lactic acidosis with metformin therapy. Arch Intern Med, 2002;162:434.