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Evaluation of Prescribing Practices
Risk of Lactic Acidosis With Metformin Therapy
Amy T. Calabrese, PharmD;
Kim C. Coley, PharmD;
Stacey V. DaPos, MS;
Dennis Swanson, MS;
R. Harsha Rao, MD, FRCP(L)
Arch Intern Med. 2002;162:434-437.
ABSTRACT
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Background The risk of lactic acidosis during metformin therapy is linked to specific
and well-documented conditions that constitute contraindications or precautions
to use of the agent. We conducted a retrospective evaluation of metformin
use to determine whether prescribing practices are in accord with published
contraindications and precautions.
Methods All patients admitted to the hospital during a 6-month period who received
at least 1 dose of metformin were identified through hospital pharmacy records.
Patient demographics and clinical characteristics were then evaluated to determine
whether metformin was prescribed to patients possessing any of the risk factors
associated with development of lactic acidosis.
Results We identified 263 hospitalizations involving 204 patients who received
at least 1 dose of metformin during inpatient admission. Patients had at least
1 absolute contraindication to metformin therapy in 71 admissions (27%). In
29 (41%) of these 71 admissions, treatment with metformin continued despite
the contraindication. The most common contraindication, elevated serum creatinine
concentration, was present or developed during 32 admissions (12%); however,
metformin use was appropriately discontinued in only 8 (25%) of these 32 patients.
Of the precautions against metformin use, concomitant administration of cationic
agents was the most common, occurring in 97 admissions (37%).
Conclusions Many patients are treated with metformin despite having clinical conditions
that place them at risk for developing lactic acidosis. To minimize this risk,
it is essential that prescribers develop a better understanding of the prescribing
guidelines for metformin.
INTRODUCTION
METFORMIN is a biguanide derivative that is used in the treatment of
type 2 diabetes mellitus. It is currently considered the initial drug of choice
for overweight patients (without contraindications) who have type 2 diabetes
mellitus with or without dyslipidemia, and it is often used in sulfonylurea-treated
patients who have not achieved their desired therapeutic goal.1
Metformin is pharmacologically related to phenformin hydrochloride, which
was withdrawn from the US market in 1976 (owing to an association with an
unacceptably high incidence of lactic acidosis). Because of structural and
pharmacokinetic differences between the compounds, the reported incidence
of lactic acidosis with metformin therapy is 10 to 20 times less than that
with phenformin use2; however, the literature
contains numerous case reports of metformin-associated lactic acidosis. To
reduce the likelihood of the development of lactic acidosis, the product labeling
for metformin identifies the clinical conditions or patient characteristics
that increase the risk of lactic acidosis.3
These precautionary conditions and contraindications are listed in Table 1.
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Table 1. Absolute Contraindications and Precautionary Conditions for
Prescribing Metformin*
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Despite the availability of prescribing guidelines, metformin continues
to be prescribed to patients at risk for lactic acidosis. For example, a 3-month
review4 of prescribing patterns in a United
Kingdom diabetes mellitus clinic concluded that more than half of the patients
prescribed metformin had conditions that predisposed them to lactic acidosis.
In another study5 from Europe, 73% of patients
receiving metformin as outpatients had contraindications to its use on admission
to the hospital.
We recently encountered a case of metformin-associated lactic acidosis
at the University of Pittsburgh Medical Center Presbyterian (UPMC Presbyterian). Despite having severe
ischemic cardiomyopathy and an ejection fraction of 15% (an absolute contraindication
to the use of metformin), the patient received the drug. This case raised
our suspicion that failure to recognize factors that place patients at risk
for lactic acidosis during metformin therapy may be more widespread than hitherto
recognized. Therefore, we set out to determine the prevalence of risk factors
for lactic acidosis in patients treated with metformin at the UPMC Presbyterian.
MATERIALS AND METHODS
The Department of Pharmacy and Therapeutics at the UPMC Presbyterian provides operational pharmacy services to 42 nursing units
using automation (unit-based dispensing cabinets and robotics) and satellite
pharmacy services. Clinical pharmacists provide advanced pharmaceutical care
in several patient care areas. The UPMC Presbyterian
uses a 3-method system to identify adverse drug events: voluntary reporting,
retrospective review of patients with E-codes (International
Classification of Diseases, Ninth Revision [ICD-9], code for adverse drug event), and computer surveillance.
This study was approved by the institutional review board of the University
of Pittsburgh. All inpatients hospitalized at the UPMC Presbyterian between March 1, 1998, and August 30, 1998, who received
at least 1 dose of metformin were identified through the hospital pharmacy
database. Patient demographics and clinical characteristics were then evaluated
to determine whether patients possessed any of the risk factors associated
with lactic acidosis (Table 1).
Comorbidities such as congestive heart failure (CHF) and chronic obstructive
pulmonary disease were identified through ICD-9 codes.
Laboratory records were reviewed to determine hepatic and renal function and
pH values. Pharmacy and billing records were reviewed to determine whether
patients received iodinated contrast dye or cationic drugs, including digoxin,
procainamide hydrochloride, quinidine, and vancomycin. The  2
test and the Fisher exact test (depending on event frequency) were used to
compare the frequency of specific risk factors in the admitting services.
RESULTS
PATIENT POPULATION
During the 6-month study, there were 263 hospital admissions involving
204 patients to whom metformin was administered. The mean age of the group
was 66 years (range, 34-93 years). The patient group was predominantly white
(81%) and was equally divided among men (n = 103) and women (n = 101). Most
admissions were to medical services, with the cardiology and general medicine
services accounting for 109 admissions (41%). Of the 204 patients, 164 were
admitted once, 28 were admitted twice, 7 were admitted 3 times, 4 were admitted
4 times, and 1 was admitted 6 times during the study. The median length of
stay was 5 days (range, 1-80 days). The discharge date was recorded as the
day after the admission date in 43 (16%) of the 263 admissions.
RISK FACTORS FOR LACTIC ACIDOSIS
There was no statistical difference in the prevalence of contraindications
(P = .18) or precautionary conditions (P = .32) in patients on the medical service vs a surgical service (Table 2). Table 3 gives the specific risk factors for lactic acidosis that
patients had at the time of hospital admission or at some point during hospitalization.
Of 204 patients receiving metformin, 126 (62%) had either an absolute contraindication
to metformin use or a condition deemed to be a precaution. Sixty-four of these
(31%) had at least 1 absolute contraindication to its use. Viewed from the
standpoint of the total number of admissions, 159 (60%) of 263 involved patients
with either an absolute contraindication or a precautionary condition, and
71 (27%) involved patients with 1 or more absolute contraindications. The
most common absolute contraindication to metformin use in our population was
an elevated serum creatinine concentration during hospitalization, occurring
in 32 admissions (12%). No patients had an ICD-9
code for CHF. Of the precautions against metformin use, concomitant administration
of cationic agents was the most common, occurring in 97 admissions (37%).
In fact, the patient who was admitted to the hospital 6 times received vancomycin
(a cationic drug that constitutes a precautionary condition) during 4 of those
admissions.
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Table 2. Prevalence of Absolute Contraindications and Precautionary
Conditions by Hospital Service*
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Table 3. Summary of the Absolute Contraindications and Precautionary
Conditions Identified in Patients Taking Metformin
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We further evaluated whether metformin therapy was continued in patients
possessing any specific risk factor for lactic acidosis. When all 71 admissions
with at least 1 absolute contraindication were considered, 29 patients (41%)
continued to receive metformin despite the contraindication. Table 4 gives the prevalence of metformin continuation by specific
risk factor and by hospital service. Metformin use was continued in 24 (75%)
of the 32 admissions during which an elevated serum creatinine concentration
was recorded. Similarly, 16 (53%) of 30 patients who received contrast dye
during an admission received metformin the day after the contrast procedure.
Of these 16 patients, a higher proportion were on the medical service compared
with a surgical service (P = .02). There were no
other statistical differences between the medical and surgical services in
the observed frequency of metformin therapy continuation despite contraindications
or precautions.
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Table 4. Prevalence of Metformin Therapy Continuation Despite the Presence
of an Absolute Contraindication or a Precautionary Condition*
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Nine patients who received metformin at some point during a hospital
admission died. In 6 of these patients, the drug was given despite the presence
of an absolute contraindication (elevated serum creatinine concentration in
4 patients and administration of contrast dye in 2 patients). In addition,
4 of these patients were older than 80 years, and 2 of them continued to receive
metformin despite a marked elevation in liver transaminase concentrations.
In 2 patients who died and 1 who survived, elevated lactate concentrations
were found (>7 mmol/L [63 mg/dL] in all patients, with a concentration as
high as 11.9 mmol/L [107 mg/dL] in 1). In these patients, all of whom had
renal dysfunction and 1 of whom had end-stage liver disease, there was a temporal
relationship between metformin administration and the elevated lactate concentrations.
Metformin-associated lactic acidosis (MALA) could not be ruled out in these
3 patients with the information available to us.
COMMENT
During the first year that metformin was available in the United States
(actually May 1995 through June 30, 1996), 47 confirmed cases of lactic acidosis
were reported to the Food and Drug Administration (FDA), which translates
to an incidence rate of 5 per 100 000.6
Forty-three (91%) of the 47 cases occurred in patients at high risk for lactic
acidosis because of preexisting cardiac disease, renal insufficiency, or chronic
obstructive pulmonary disease with hypoxia. Twenty (43%) of these 47 patients
died.
Although the reported incidence of MALA is rare, the product labeling
for metformin states that the drug is contraindicated in patients with risk
factors for lactic acidosis.3 Metformin increases
intestinal lactate production and contributes to the hyperlactatemia seen
in patients who accumulate metformin in the setting of a hypoxic event or
defective lactate elimination (renal or hepatic failure).7
Despite this, it remains unclear whether metformin is a contributing cause
of lactic acidosis or if it is merely a drug with a coincidental link to lactic
acidosis. Nearly all reported cases of MALA occurred in patients who were
already at high risk for lactic acidosis.7-8
However, it is impossible to refute with absolute confidence that such a relationship
exists based on the currently available data. Reliance on incidence rates
of MALA as reported to the FDA or equivalent governmental agencies in other
countries is confounded by the observation that the FDA may actually receive
an official report of just 1% of all serious or fatal adverse drug reactions.9
The authors of a retrospective review of a large electronic health maintenance
organization database determined that the overall rate of lactic acidosis
in patients with type 2 diabetes mellitus before the availability of metformin
(1993-1994) was similar to the incidence of MALA (as reported to the FDA in
1995-1996).8 A major limitation of this study,
however, is that the approach used may underestimate the true magnitude of
the association between metformin and lactic acidosis; the metformin-treated
group may have been biased in favor of low-risk patients because of the known
association of the drug with lactic acidosis, whereas the retrospective data
set comprised "all-comers." In other words, the incidence of MALA might be
higher if all individuals with diabetes mellitus are deemed eligible for the
drug.
It remains important that physicians, nurse practitioners, physician
assistants, and other health care professionals (including nurses and pharmacists)
responsible for drug delivery remain aware of patient-specific factors that
increase a patient's risk of MALA. Our analysis leads to the conclusion that
metformin continues to be prescribed to patients who are at high risk for
lactic acidosis. What is particularly alarming is the fact that the problem
may be even more widespread than is evident from our data. The prevalence
of risk factors in our study population was most likely underestimated for
several reasons, most having to do with the retrospective nature of the study
design. First, given patient age and concurrent medications taken, it is likely
that CHF was a comorbidity for some, if not many, patients. Yet, none of the
patients in the study were discharged from the hospital with an ICD-9 code for CHF. It is likely that CHF was not coded unless it was
the medical problem that directly resulted in the current hospitalization.
Second, data linking metformin use in patients with other relative contraindications,
such as alcohol abuse, or patients receiving surgical procedures were not
collected. Third, we were unable to ascertain whether patients discharged
the same day as a procedure that required intravascular contrast material
may have restarted metformin therapy before completion of the required 48-hour
waiting period following dye administration. Thus, a limitation of this study
is that the actual prevalence of risk factors may be significantly higher
than that identified in this patient population.
It is also important to recognize that our study was designed neither
to verify that metformin therapy causes lactic acidosis nor to suggest that
metformin use should be avoided in all patients with relative precautions
to the drug. Rather, we were interested in determining whether prescribers
were complying with the labeled contraindications and precautions to the use
of metformin. In this regard, we determined that at the time of or some time
during admission to the hospital, approximately 1 in 4 patients developed
at least 1 absolute contraindication to the drug, and in nearly half of these,
metformin therapy was continued despite the contraindication. This failure
to recognize contraindications was just as likely to occur on a medical service
(by those who may be "routine prescribers" of metformin) as it was on a surgical
service (by those who may be less familiar with the drug).
Several relatively safe and effective drugs (terfenadine, astemizole,
mibefradil dihydrochloride, bromfenac sodium, and cisapride) have recently
been withdrawn from the US market mainly because they were used in patients
with labeled contraindications.10-11
The US FDA has said that additional drugs will likely be removed from the
market unless there is a change in the way health care professionals regard
safety warnings.10 We believe that compliance
with metformin prescribing guidelines is essential not only if MALA is to
remain a rare entity but also if metformin is not to have a similar fate.
AUTHOR INFORMATION
Accepted for publication June 6, 2001.
This work was presented in part as a poster at the American Diabetes
Association 60th Scientific Sessions, San Antonio, Tex, June 12, 2000.
Corresponding author: Amy T. Calabrese, PharmD, Department of Pharmacy
and Therapeutics, University of Pittsburgh Medical Center Health System, 302
Scaife Hall, 200 Lothrop St, Pittsburgh, PA 15213.
From the Department of Pharmacy and Therapeutics, University of Pittsburgh
(Drs Calabrese and Coley and Mr Swanson); the Department of Pharmacy and Therapeutics,
University of Pittsburgh Medical Center Health System (Dr Calabrese and Ms
DaPos); and the Division of Endocrinology, Department of Medicine, University
of Pittsburgh Medical Center (Dr Rao), Pittsburgh, Pa. Dr Rao is a member
of the Speakers Bureau of Bristol Myers Squibb and has received honoraria
for speaking at educational programs sponsored by the company.
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