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Metformin and risk of cardiovascular events J. A. Johnson et alReduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes
J. A. Johnson*†, S. H. Simpson*, E. L. Toth*‡ and S. R. Majumdar*§
Abstract
*Institute of Health Economics, Edmonton, Alberta,
Metformin therapy reduces microvascular complications in Type 2 dia-
†Department of Public Health Sciences, ‡Division of
betes; questions remain, however, regarding its impact on macrovascular events.
Endocrinology & Metabolism, Department of
This study examined metformin use in relation to risk of cardiovascular-related
Medicine and §Division of General Internal Medicine, Department of Medicine, University of
We conducted a retrospective cohort analysis, using Saskatchewan
Health administrative databases to identify new users of oral antidiabetic drugs. Subject groups were defined by medication use during 1991–1999: sulphonylu-rea monotherapy, metformin monotherapy, or combination therapy. Deathsand non-fatal hospitalizations recorded during the study period were identifiedas cardiovascular-related from ICD-9 codes. The main outcome was a compos-ite of first non-fatal hospitalization or death. Standard multivariate techniques,including propensity scores, were used to adjust for potential confounding. Multivariate Cox proportional hazard models were used to examine the rela-tionship between metformin use and the composite endpoint.
Metformin monotherapy was associated with a lower risk of the com-
posite endpoint (adjusted hazard ratio 0.81; 95% confidence interval 0.68,0.97) compared with sulphonylurea monotherapy. Combination therapy withmeformin and a sulphonylurea was associated with lower mortality, but hadsimilar hospitalization rates, to sulphonylurea monotherapy. Conclusions
Metformin monotherapy was associated with a lower risk of
cardiovascular-related morbidity and mortality, and combination metformin andsulphonylurea therapy was associated with a reduced risk of fatal cardiovascu-lar events, when compared with sulphonylurea monotherapy. Keywords
diabetes mellitus, metformin, morbidity and mortality, propensity score
common condition in Type 2 diabetes [2]. Since hyperinsulinaemia
Introduction
may aggravate other metabolic disorders, including hyper-
Metformin, as monotherapy or in combination with sulpho-
lipidaemia [2] and endothelial dysfunction [3], metformin may
nylureas, improves glycaemic control in people with Type 2
provide protection from cardiovascular disease compared with
diabetes mellitus [1]. It appears that metformin improves insulin
sulphonylurea therapy, which acts by increasing insulin levels.
sensitivity, which in turn may reduce hyperinsulinaemia—a
The effect of metformin on clinical outcomes has been
evaluated in the United Kingdom Prospective Diabetes Study(UKPDS) [4] and in retrospective observational studies [5–7]. The observed association between metformin and macrovas-
Correspondence to: Dr Jeffrey A. Johnson, #1200, 10405 Jasper Ave, Edmonton, AB, Canada T5J 3 N4. e-mail: jeff.johnson@ualberta.ca
cular morbidity and mortality continues to be a topic of much
2005 Diabetes UK. Diabetic Medicine, 22, 497– 502
Metformin and risk of cardiovascular events • J. A. Johnson et al
controversy [8,9]. The UKPDS demonstrated that metformin
Subjects and methods
use in obese patients with Type 2 diabetes reduced all-causemortality and diabetes-related endpoints [4]. However, in
Subjects
subjects failing after an average of 7 years of sulphonylureamonotherapy, addition of metformin was associated with an
The Saskatchewan Prescription Drug Plan database was used to
increased risk of all-cause and diabetes-related mortality com-
identify new users of oral antidiabetic drugs. The adminis-
pared with continuation of sulphonylurea monotherapy [4].
trative healthcare databases from Saskatchewan were used
An increased risk of mortality with combination metformin
because they provide comprehensive healthcare information
and sulphonylurea therapy was also reported in several sub-
for all registered beneficiaries in the province [13]. Essentially
sequent observational studies [5–7]. These studies were rela-
all (> 90%) residents of the province are beneficiaries of
tively small, however, and limited by the inability to control
Saskatchewan Health; exceptions include registered Indians,
federal inmates and employees of the military and Royal Cana-dian Mounted Police, whose prescription benefits are adminis-
We recently reported a population-based analysis demon-
tered by federal programmes. Saskatchewan residents aged
strating that metformin, either alone or in combination with
30 years or older were eligible for inclusion if they had continu-
sulphonylurea, was associated with reduced all-cause and
ous prescription drug coverage in Saskatchewan for at least
cardiovascular mortality compared with sulphonylurea mono-
1 year prior to the index date (i.e. date of the first claim for an
therapy [10]. We evaluated a cohort of new users of oral anti-
oral antidiabetic drug in the index period). New users of oral
diabetic drugs and therefore were able to control for duration
antidiabetic drugs were identified as subjects with a prescrip-
of therapy for diabetes. Several questions remained unan-
tion claim for a sulphonylurea or metformin during the index
swered, however. For example, were observations limited by
period of January 1991 to December 1996, and no prescription
selection bias (i.e. ‘sicker’ patients prescribed sulphonylureas,
claims for antidiabetic drugs within the previous year. Subjects
a form of confounding by indication), and do the benefits
were excluded if they had any record of insulin use or if they
of metformin therapy extend to non-fatal cardiovascular
had less than 1 year between the first and last dispensationrecords for oral antidiabetic drugs. Exposure status was further
events. In the absence of randomized controlled trials,
refined by excluding subjects who did not obtain sufficient
observational studies provide an alternative method for
medication to provide the minimum recommended daily
resolving clinically important questions [11,12]. The pur-
dose during one or more 6-month interval of their follow-up
pose of this study was to extend our mortality analyses by
evaluating the association between metformin and rates of
Subjects included in the study were grouped according to
fatal and non-fatal cardiovascular events for those with Type
their oral antidiabetic drug use recorded in the Saskatchewan
Prescription Drug Plan database. Subjects who received either
Figure 1 Flowchart of subject selection. *Minimum recommended daily doses: acetohexamide 250 mg; chlorpropamide 100 mg; glibenclamide 2.5 mg; tolbutamide 500 mg; tolazamide 100 mg; metformin 250 mg.
2005 Diabetes UK. Diabetic Medicine, 22, 497– 502 Table 1 International Classification of Diseases 9th Revision (ICD-9)
would have a minimum CDS of 2 because they had to be using
oral antidiabetic drugs; use of lipid-lowering agents contributes
an additional score of 1 and antihypertensives contribute a
score of 2 (if an antihypertensive other than ACE inhibitor) or1 (for β-blockers and diuretics) [16]. Interaction terms between
each variable and treatment group were also examined; how-
ever, these terms were not included in the final models because
none reached statistical significance (P < 0.1).
Survival curves for the time to first non-fatal hospitalization
or death were generated using the corrected group prognosis
method [17,18]. In this method, the first step is to estimate sur-
vival curves for each unique combination of covariates. The
final survival curve is the weighted average of all these indi-
vidual curves, with the weighting based on number of individualsat each level of covariate [18]. To fit the data into the correctedgroup prognosis model, continuous variables (i.e. age, chronicdisease score) were collapsed to dichotomous variables.
sulphonylureas or metformin exclusively during follow-up
Data used for this observational study reflect actual practice
were categorized as sulphonylurea monotherapy or metformin
in Saskatchewan during 1991–1999 in that the prescription for
monotherapy, respectively. Subjects were categorized in the
sulphonylureas and metformin was made at the discretion of
combination therapy group if they received both metformin
the clinician, rather than by randomization. Therefore, we were
and sulphonylureas and if these drugs were used concurrently
interested in adjusting for potential selection bias because
for at least 50% of their follow-up. All study subjects were fol-
group assignment in this study was based on medication use
lowed prospectively from index date until death, study exit (i.e.
[19]. Propensity scores, intended to represent the likelihood of
moved out of Saskatchewan), or 31 December 1999.
receiving one of the treatments given the individual’s charac-teristics, were calculated to control for potential differences
Outcomes
between groups [20–22]. Separate propensity scores were gen-erated, using logistic regression, for metformin monotherapy
The primary outcome was the composite endpoint of fatal
vs. sulphonylurea monotherapy and combination therapy vs.
or non-fatal cardiovascular-related events (Table 1). Cause of
sulphonylurea monotherapy. Propensity scores were generated
death was ascertained through the computerized vital statistics
using age, age2, sex, CDS, CDS2, current use of nitrates, as well
file of Saskatchewan Health. Non-fatal events were defined as
as interaction terms among all variables. The generated propens-
any cardiovascular-related hospitalization in which the patient
ity scores were then included as an additional covariate in the
was discharged alive. Hospitalizations were classified as
cardiovascular-related based on the primary diagnosis code(ICD-9) from hospital separation records, as it is the diagnosismost responsible for length of stay and resource utilization.
As a composite endpoint, only the first non-fatal or fatal
A total of 12 188 Saskatchewan residents were identified as
event was counted for each individual. The fatal and non-fatal
new users of oral antidiabetic drugs during the index period
event rates were analysed separately as secondary outcomes.
(Fig. 1). Of these, 1443 were excluded because they were dis-pensed insulin during their follow-up and 2009 had less than
Statistical analysis
1 year of dispensation records for oral antidiabetic drugs. Afurther 3034 subjects were excluded because their average
Comparisons between groups were evaluated using univariate
daily supply of oral antidiabetic drug was below the minimum
ANOVA for continuous variables and χ for categorical variables. Cox proportional hazard models were used to evaluate the re-
recommended daily dose. Of the 2641 subjects identified as
lationship between metformin use (either as monotherapy or in
taking both sulphonylurea and metformin, only 1081 sub-
combination with sulphonylureas) and time to first event. In all
jects used both drugs concurrently for at least 50% of their
models, the sulphonylurea monotherapy group served as the
follow-up. There were 2138 subjects in the sulphonylurea
monotherapy group and 923 subjects in the metformin
The following potential confounding variables were included
monotherapy group. Table 2 provides demographic informa-
in the adjusted analyses: age, sex, nitrate use, and a Chronic
tion for all 4142 subjects included in the analysis.
Disease Score (CDS). Nitrate use was included because it is a
A total of 381 subjects died from cardiovascular causes and
marker for established coronary artery disease [14,15]. The
715 were hospitalized at least once for cardiovascular reasons
CDS uses pharmacy dispensation information for specific drug
during the follow-up period (Table 3). Subjects in the metformin
classes to estimate a burden of comorbidities, and has provedvalid in predicting hospitalization and mortality [16]. The CDS
monotherapy group had the lowest non-fatal hospitalization
is the sum of all chronic diseases identified from drug therapy
rate for cardiovascular causes (53.7 hospitalizations per 1000
during an observation period, including incremental therapies
person-years) compared with sulphonylurea monotherapy
for cardiovascular risk. For example, all subjects in this study
users (75.3 per 1000 person-years; P < 0.05) and compared
2005 Diabetes UK. Diabetic Medicine, 22, 497– 502
Metformin and risk of cardiovascular events • J. A. Johnson et alTable 2 Subject demographics
*ANOVA (P < 0.01). †χ2 (P < 0.01). Figure 2 Adjusted (for age, sex, chronic disease score, nitrate use)
with combination therapy users (90.2 per 1000 person-years;
survival curves illustrating the relationship between metformin use and
P < 0.05). Non-fatal cardiovascular-related hospitalization
time to first non-fatal hospitalization or death.
rates were similar for sulphonylurea monotherapy users andcombination therapy users (P = 0.08).
hospitalizations were similar for sulphonylurea monotherapy
In the unadjusted analyses (Table 3), metformin, alone or in
and combination therapy groups (P = 0.32).
combination with sulphonylurea, was associated with a lower
Following adjustment for patient and treatment factors,
risk of the composite endpoints [hazard ratio (HR) 0.67; 95%
metformin monotherapy continued to be associated with a
confidence interval (CI) 0.56, 0.80 and HR 0.80; 95% CI 0.69,
lower risk of the composite endpoint (Fig. 2) as well as fatal
0.93, respectively]. Metformin, either alone or in combination,
and non-fatal cardiovascular events. Metformin in combina-
was also associated with a lower risk of mortality from cardio-
tion with sulphonylurea continued to be associated with a
vascular causes. Metformin monotherapy was associated
lower risk of mortality from cardiovascular causes. Addition
with a lower risk of non-fatal cardiovascular hospitalizations
of a propensity score to the models did not make a substantial
(HR 0.75; 95% CI 0.61, 0.93); event rates for cardiovascular
change to observations from the adjusted model ( Table 3). Table 3 Cardiovascular-related event rates Non-fatal cardiovascular hospitalization‡
*Adjusted for age, sex, chronic disease score, nitrate use. †Sulphonylurea monotherapy group served as reference group. ‡The first non-fatal cardiovascular hospitalization was used in the hazard ratio for subjects with multiple non-fatal hospitalizations. §The first non-fatal cardiovascular hospitalization was used for subjects with both a non-fatal hospitalization and fatal event (i.e. these subjects were not double counted).
2005 Diabetes UK. Diabetic Medicine, 22, 497– 502
coronary artery disease. Additionally, metformin is likely to
Discussion
be preferentially used in obese patients [2,4], who have an
Randomized clinical trials have demonstrated the benefits
increased cardiovascular risk. If this were the case, we would
of metformin therapy for lowering elevated blood glucose
have expected an increased event rate in the metformin group;
and reducing the risk of microvascular complications [1,2,4].
therefore, had we been able to control for BMI, it is possible
However, cardiovascular disease is the leading cause of mor-
that the risk reduction would have been even greater. Further-
bidity and mortality associated with Type 2 diabetes [23–26]
more, administrative data of drug dispensations do not assure
and the impact of oral antidiabetic therapy on macrovascular
the exact level of drug consumption and therefore exposure.
complications and cardiovascular disease has been the subject
We restricted our current analyses to individuals with evidence
of much discussion [4 – 8]. We previously reported reductions
of ongoing use of medication above minimum recommended
in mortality associated with metformin use, either alone or in
dosages, which provides a reasonable level of confidence in the
combination with sulphonylureas using a retrospective cohort
design, and administrative data from Saskatchewan Health
Additionally, in our analyses, we identified new users of
[10]. After controlling for age, sex, comorbidities, and
oral antidiabetic agents; we could not, therefore, control for
nitrate use (a proxy for established coronary artery disease), we
duration of diabetes not treated with oral agents prior to our
observed statistically significant and clinically important
identification of cases. Nonetheless, we have no reason to
reductions in all-cause and cardiovascular-related mortality.
believe that this duration would be different for individuals
Using the same cohort as our previous study, but further
treated initially with sulphonylureas vs. metformin, and thus,
refining our drug exposure definitions and including a pro-
it is unlikely to affect our risk estimates. Finally, we ascertained
pensity score to minimize the role of unmeasured (residual)
non-fatal outcomes as those resulting in hospitalization. We
confounding, the results of this study are consistent with our
recognize that this probably underestimates the rate of all non-
previous report, and extend the observations to include non-
fatal cardiovascular events by excluding milder cardiovascular
fatal events. In multivariate analyses, the composite endpoint
events. Again, however, there is no reason to expect that this
of cardiovascular-related non-fatal hospitalizations and
underestimation would be systematically different between the
mortality occurred less frequently in metformin monotherapy
cohorts under study, and therefore, it is unlikely to bias our
users compared with sulphonylurea monotherapy users.
Combination sulphonylurea and metformin therapy users
The association between hyperinsulinaemia, hyperlipidae-
appeared to have a reduced risk of cardiovascular-related
mia [2], endothelial dysfunction [3], and cardiovascular
non-fatal and fatal events compared with sulphonylurea
morbidity and mortality is well recognized [23 –26]. Pharma-
cological therapy that increases insulin sensitivity should
The observed event rates in the current analysis may also
have a beneficial effect on cardiovascular outcomes in Type 2
address, to some extent, concerns regarding confounding
diabetes in addition to its beneficial effects on diabetes out-
by indication in our previous analysis [10]. For example,
comes. In the present study, subjects receiving metformin
sulphonylureas may have been prescribed for subjects with
monotherapy were less likely to be admitted to hospital for or
‘advanced’ disease and therefore at higher risk of cardiovascular-
die from cardiovascular events compared with sulphonylurea
related hospitalization or death. Following this hypothesis,
monotherapy users. Subjects receiving combination therapy
subjects receiving combination therapy should be even ‘sicker’,
were also less likely to die from cardiovascular causes, but had
yet we observed a lower mortality rate than sulphonylurea
a similar rate of non-fatal cardiovascular events. This finding
monotherapy users, despite the former having the highest hos-
would be consistent with the possibility that metformin therapy
pitalization rate of our three study groups. Furthermore, it is
may reduce the extent or severity of cardiovascular disease [2].
well recognized that glycaemic control in patients with Type 2
Our observations refute previous studies suggesting that the
diabetes progressively worsens over time [27], and it is unlikely
combination of metformin and sulphonylurea is associated
that continued monotherapy provides sustained glycaemic
with increased risk of morbidity and mortality in Type 2 dia-
control [28]. Thus, our data suggest that even in the face of
betes. Indeed, our results indicate that metformin is associated
progressively deteriorating glycaemic control, metformin use
with reduced cardiovascular morbidity and mortality in
was associated with a reduction in fatal and non-fatal cardio-
people with Type 2 diabetes. Until randomized trials are con-
ducted to explore these issues further, these observational data
As with other studies based solely on administrative data-
provide the most valid information available for clinical
bases, there are several limitations inherent in the available
decision-making, and support the long-term safety and effect-
data that must be recognized. Because our analysis was based
iveness of metformin, alone or in combination, in patients
entirely on administrative databases, and is limited by a lack of
direct clinical information, we could not control for level ofglycaemic control, body mass index (BMI), or other modifi-
Competing interests
able cardiovascular risk factors (e.g. smoking). However, wecontrolled for age, gender, comorbidity, and the presence of
2005 Diabetes UK. Diabetic Medicine, 22, 497– 502
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2013 Patient Medical History Date of Birth: _____________________ Emergency Contact/Phone:________________________ Name: ___________________________ Pharmacy:____________________________________ Family Physician: _________________________ Referring Doctor: _______________________________ Do you wear? Glasses Contact Lenses (What type?) _______________________ □ No Glasses or Con
Melissenextrakt wirkt zweifach gegen Lippenbläschen Seit Jahren wird geforscht, womit dem unangenehmen Herpes simplex-Virus – Auslöser schmerzhafter Lippenbläschen – zu Leibe gerückt werden kann. Eine gute Nachricht kommt jetzt aus dem Universitätsklinikum Heidelberg*. Virologen und Biologen haben nachgewiesen, dass Melissenextrakt in gleich doppelter Weise einem Herpesausbruch