DIABETES, LIPIDS AND METABOLISM
Effects of metoprolol and carvedilol on pre-existing and new
onset diabetes in patients with chronic heart failure: data from
the Carvedilol Or Metoprolol European Trial (COMET)
Christian Torp-Pedersen, Marco Metra, Andrew Charlesworth,
Phillip Spark, Mary Ann Lukas, Philip A Poole-Wilson,
Karl Swedberg, John G F Cleland, Andrea Di Lenarda,
Willem J Remme, Armin Scherhag, for the COMET investigators
............................................................... ............................................................... .....
See end of article for
Professor C Torp-Pedersen,
Department of Cardiology,
Hospital, 2400 Copenhagen
NV, Denmark; email@example.com
Accepted 7 November 2006
Published Online First
18 January 2007
Heart 2007;93:968–973. doi: 10.1136/hrt.2006.092379
Background: b Blocker treatment may worsen glucose metabolism.
Objective: To study the development of new onset diabetes in a large cohort of patients with heart failure
treated with either metoprolol or carvedilol.
Design: Prospective and retrospective analysis of a controlled clinical trial.
Setting: Multinational multicentre study.
Patients: 3029 patients with chronic heart failure.
Interventions: Randomly assigned treatment with carvedilol (n=1511, target dose 50 mg daily) or
metoprolol tartrate (n=1518, target dose 100 mg daily).
Results: Diabetic events (diabetic coma, peripheral gangrene, diabetic foot, decreased glucose tolerance or
hyperglycaemia) and new onset diabetes (clinical diagnosis, repeated high random glucose level or glucose
lowering drugs) were assessed in 2298 patients without diabetes at baseline. Diabetic events occurred in
122/1151 (10.6%) patients in the carvedilol group and 149/1147 (13.0%) patients in the metoprolol group
(hazard ratio (HR)=0.78; 95% confidence interval (CI) 0.61 to 0.99; p=0.039). New onset diabetes was
diagnosed in 119/1151 (10.3%) v 145/1147 (12.6%) cases in the carvedilol and metoprolol treatment
groups (HR=0.78, CI 0.61 to 0.997; p=0.048), respectively. Patients with diabetes at baseline had an
increased mortality compared with non-diabetic subjects (45.3% v 33.9%; HR=1.45, CI 1.28 to 1.65). Both
diabetic and non-diabetic subjects at baseline had a similar reduction in mortality with carvedilol compared
with metoprolol (RR=0.85; CI 0.69 to 1.06 and RR=0.82; CI 0.71 to 0.94, respectively).
Conclusion: A high prevalence and incidence of diabetes is found in patients with heart failure over a course
of 5 years. New onset diabetes is more likely to occur during treatment with metoprolol than during treatment
The presence of diabetes increases the risk of death by 50% in
patients with heart failure, in particular among women2and
patients with ischaemic cardiomyopathy.3–5Diabetes in patients
with heart failure is therefore of major concern. b Blockers are
an important treatment for heart failure in patients whether or
not they have diabetes,6despite reported increases in blood
glucose of up to 1.55 mmol/l,7and HbA1cby as much as 1%.8
These changes may potentially be of clinical importance in
patients with heart failure.
Carvedilol has been reported to have a more favourable effect
on glucose metabolism than other b blockers, and it stabilised
HbA1c, improved insulin sensitivity and slowed development of
microalbuminuria compared with metoprolol in one large trial
in hypertension.9The Carvedilol Or Metoprolol European Trial
(COMET)10 11demonstrated that carvedilol at a target dose of
50 mg daily reduced mortality in patients with heart failure
compared with metoprolol tartrate at a target dose of 100 mg
daily. The main aim of this report was to determine whether
carvedilol was associated with a different incidence of diabetes
in new onset diabetes compared with metoprolol in patients
with heart failure.
iabetes affects 10–30% of patients with heart failure.1
When patients with prediabetic glucose abnormalities are
also included the combined prevalence increases to 40%.1
COMET was a randomised, double blind, parallel group trial
comparing carvedilol with metoprolol tartrate for the treatment
of chronic heart failure accompanied by left ventricular systolic
dysfunction. The study design and primary results have been
described in detail previously.10 11A total of 3029 patients with
chronic heart failure were randomised at 316 centres in 15
European countries. Patients were recruited between December
1996 and January 1999, and follow-up was concluded in
November 2002. The study was conducted according to the
Declaration of Helsinki, was approved by relevant ethical
boards and the patients gave informed consent to participation.
In brief, inclusion required the presence of symptomatic
chronic heart failure (NYHA class II–IV), a need for diuretic
treatment, at least one admission to hospital for a cardiovas-
cular problem within the past 2 years, stable concomitant
medication including ACE inhibitors (if tolerated) for at least
4 weeks and left ventricular ejection fraction below 35%. Major
exclusion criteria were requirement for intravenous inotropic
treatment, current treatment with calcium channel blockers (of
the diltiazem or verapamil class), amiodarone (.200 mg/day)
or class I antiarrhythmic drugs, or administration of any
This paper is freely available online
under the BMJ Journals unlocked scheme,
investigational drug within the preceding 30 days. We also
excluded patients with a contraindication to a b blocker, acute
arrhythmia within the previous 2 months, uncontrolled hyper-
tension, haemodynamically significant valve disease, known
drug or alcohol abuse, poor compliance and, finally, any serious
disease that might complicate treatment or reduce life
At randomisation patients were assigned to either 3.125 mg
carvedilol twice daily or 5 mg metoprolol tartrate twice daily.
The dose of each b blocker was to be doubled at 2-week
intervals towards a target dose of 25 mg carvedilol twice daily
or 50 mg metoprolol tartrate twice daily.
End points: definitions
Diabetes was considered present at baseline if reported by the
investigator as a concomitant disease. It included patient
reporting and notes in hospital files.
The following definitions were used in the analyses: a
diabetes related adverse event was a prespecified end point
and was defined as the reporting, among patients without
diabetes at baseline, of at least one of the following adverse
events (diabetes, diabetic coma, peripheral gangrene/diabetic
foot, decreased glucose tolerance or hyperglycaemia).
Because the diabetes related adverse events also included
events (hyperglycaemia, decreased glucose tolerance) that were
not necessarily diabetes, we subsequently defined a new end
point retrospectively—new onset diabetes. This was considered
1. A clinical diagnosis of diabetes was reported. If the
investigator reported an adverse event coded as diabetes
mellitus or diabetic coma, or if the patients had started
chronic medical treatment with insulin or oral glucose
If the patient had at least two random blood glucose
readings above 11.1 mmol/l. Random glucose was mea-
sured four times during the first year and thereafter once a
year. Random glucose was measured by the investigator
Diabetes at baseline
No diabetes at baseline
p Value (diabetes
versus no diabetes)
Age (years), mean (SD)
Gender (% male)
Race (% white)
Body mass index (kg/m2), mean (SD)
Systolic BP (mm Hg), mean (SD)
Diastolic BP (mm Hg), mean (SD)
Heart rate (bpm), mean (SD)
NYHA class (%)
Duration CHF (months), mean/median
Aetiology CHF (%)
Ischaemic heart disease
Previous valve surgery
LVEF, mean (SD)
NT-proBNP (pg/ml), median
Haemoglobin level (g/l), mean (SD)
Serum creatinine (mmol/l), mean (SD)
Blood glucose (mmol/l), mean (SD)
Previous MI (%)
CAD (confirmed by angiography) (%)
Current angina (%)
Previous angioplasty (%)
Previous CABG (%)
ECG findings (%)
ACE inhibitors (%)
Angiotensin receptor antagonists (%)
Aldosterone antagonists (%)
b Blockers (%)
Lipid lowering agents (statins) (%)
CHF, chronic heart failure; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal prohormone brain natriuretic peptide.
New onset diabetes: COMET 969
using the local laboratory. Blood glucose was requested, but
in some cases plasma glucose may have been reported. For
this reason we used the conservative estimate of
11.1 mmol/l as the cut-off point.
If adverse event reporting was unclear/contradictory from
the original case report forms (such as the reporting of a
single high blood glucose reading) an additional page was
sent to the investigators requesting to review the patient
file and confirm the existence of diabetes, give the date
diabetes was diagnosed and tick the following possibilities:
need for diabetic drug treatment, repeated high blood
glucose results, a positive oral glucose tolerance test,
repeated high fasting glucose. Only when a date (at least
month/year) and at least one of the tick boxes was
answered as ‘‘yes’’ was the patient classified as diabetic.
Differences between patients with or without diabetes at
baseline were assessed using t tests for continuous variables
and the x2test for categorical data. Kaplan–Meier mortality
estimates were calculated by treatment for those with or
without diabetes at baseline. Time to event analyses were
performed using Cox proportional hazard models. When time
to first diabetes related adverse event or new onset diabetes was
examined patients were censored at the time of death. The
multivariate model for new onset diabetes was produced using
forward and backward stepwise procedures, with a threshold
probability of 0.05. The relationship between mortality and
diabetes (diabetes at baseline and new onset diabetes) was
assessed using diabetes as a time dependent covariate. All
significant (obtained using stepwise procedures) baseline
prognostic factors were included in this model. Model
assumptions (proportional hazard assumption, linearity of
continuous variables and lack of interaction) were tested and
Of the 3029 patients randomised in COMET, 731 (24.1%) had
diabetes at baseline. Table 1 shows the baseline demographics
of patients with and without diabetes. The patients with and
without diabetes at baseline differed significantly from each
other, but in both groups patients were well matched with
respect to treatment allocation.
New onset diabetes
Analysis of new onset diabetes was performed only in patients
without diabetes at baseline. Patients without diabetes at
baseline had a follow-up of 47–72 months. A diabetes related
adverse event occurred in 271 patients and new onset diabetes
was detected in 264 patients. There were significant differences
in the rates of these events between the patients randomised to
carvedilol and metoprolol. Thus, 122 patients receiving carve-
dilol and 149 patients receiving metoprolol had diabetes related
adverse events (hazard ratio (HR)=0.78; 95% confidence
intervals (CI) 0.61 to 0.99; p=0.039) and 119 patients receiving
carvedilol and 145 patients receiving metoprolol developed new
onset diabetes (HR=0.78, 95% CI 0.61 to 0.997; p=0.048,
fig 1). The Kaplan–Meier estimates that 28 patients would be
need to be treated for 5 years to avoid new onset diabetes.
Diabetes related adverse events included the development of
diabetes in 100/1151 (8.7%) patients receiving carvedilol and in
116/1147 (10.1%) patients receiving metoprolol, decreased
glucose tolerance or hyperglycaemia alone in 19/1151 (1.7%)
and 33/1147 (2.9%) patients, and peripheral gangrene/diabetic
foot alone in 3/1151 (0.3%) and 0/1147 (0.0%) patients
receiving carvedilol and metoprolol, respectively. The diagnosis
of new onset diabetes was based on a clinical diagnosis in 109/
1151 (8.3%) patients receiving carvedilol and 130/1147 (11.3%)
patients receiving metoprolol, on the addition of glucose
lowering medical treatment alone in 3/1151 (0.3%) and 9/
1147 (0.8%) patients and solely based on the finding of at least
11.1 mmol/l in 7/1151 and 6/1147 patients receiving carvedilol
and metoprolol, respectively.
Table 2 shows those factors that independently predicted the
risk of developing diabetes in a multivariable model. New onset
diabetes was more likely to occur in the patients with a high
body mass index, a history of hypertension and NYHA class IV,
and less likely to occur in the patients with NYHA class III and
higher serum creatinine. Metoprolol remained independently
associated with a greater likelihood of developing new onset
diabetes in this analysis.
During the trial, blood glucose was measured every 4 months;
fig 2 shows the blood glucose measurements during the study
in the patients subdivided by treatment and by the presence of
diabetes at baseline. There was no statistically significant
difference between patients treated with carvedilol and
metoprolol, but there was an overall significant trend for an
increase in random blood glucose over the course of the trial in
patients without diabetes at baseline (p,0.0001, with repeated
measures analysis including only patients with 4 years com-
plete laboratory follow-up).
Percentage with end point
0.614 to 0.997 0.0477
Development of new onset diabetes.
variables in table 1 were used in development of the model.
Only significant variables were included in the final model
Multivariable risk of new onset diabetes. All
(95% CI)p Value
Carvedilol v metoprolol
q BMI (per unit)
NYHA III v II
NYHA IV v II
q Haemoglobin (per g/l)
Creatinine (mmol/l) .90 v
Creatinine (mmol/l) .110 v
q Glucose (per mmol/l)
0.756 (0.587 to 0.973)
1.1 (1.075 to 1.125)
0.757 (0.582 to 0.986)
1.956 (1.047 to 3.656)
2.113 (1.581 to 2.823)
1.145 (1.051 to 1.247)
0.735 (0.545 to 0.991)
0.735 (0.535 to 1.011)
1.561 (1.479 to 1.648)
970 Torp-Pedersen, Metra, Charlesworth, et al
Patients with diabetes at baseline had an increased risk of
death compared with patients without diabetes (45.3% v 33.9%;
HR=1.45; CI 1.28 to 1.65; p,0.0001). Figure 3 shows mortality
curves from the whole COMET population subdivided by
treatment allocation and the presence of diabetes at baseline.
The 5 year mortality rate for patients without diabetes at
baseline was 32.7% (95% CI 29.8% to 35.7%) for those receiving
carvedilol and 38.1% (95% CI 35.1% to 41.2%) for those
receiving metoprolol. In patients with diabetes at baseline the
5 year mortality rate was 44.0% (95% CI 38.7% to 49.7%) for
those receiving carvedilol and 50.1% (95% CI 44.7% to 55.7%)
for those receiving metoprolol. Both diabetic and non-diabetic
subjects at baseline had similar risk reductions for mortality in
favour of carvedilol compared with metoprolol (RR=0.85; CI
0.69 to 1.06; p=0.147 for diabetic subjects and RR=0.82; 95%
CI 0.71 to 0.94; p=0.006 for non-diabetic subjects, respec-
tively). There was no interaction between baseline diabetic
status and treatment with either carvedilol or metoprolol
Both diabetes and treatment allocation were independently
related to all-cause mortality in a multivariate analysis that
included both diabetes at baseline and new onset diabetes as
time dependent variables (HR=0.832; 95% CI, 0.739 to 0.936;
p=0.0022 for carvedilol versus metoprolol and HR=1.298;
95% CI 1.147 to 1.469; p,0.0001 for diabetes (baseline and new
onset) versus no diabetes). The prognostic value of these
variables was maintained in a multivariate analysis including
all the clinical variables independently associated with an
increased mortality in COMET (table 3).
This study demonstrates that treatment with carvedilol is
associated with less development of new onset diabetes in
patients with heart failure compared with treatment with
metoprolol tartrate. The study further demonstrates that not
only is the prevalence of diabetes high in patients with heart
failure but also the incidence is high, amounting to 10–15%
over 5 years.
Chronic administration of b blockers is now mandatory in
patients with chronic heart failure who do not have contra-
indications to their use.12However, these agents are associated
with a reduction in insulin sensitivity and with an increased
risk of diabetic complications.7 8Carvedilol has more favourable
metabolic effects in diabetic patients than traditional b
blockers9 13and reduces mortality in patients with chronic
heart failure more than metoprolol tartrate.10It was therefore
important to assess whether the specific pharmacological
characteristics of carvedilol might influence the development
of diabetic complications and new onset diabetes and deter-
mine its effects on mortality, compared with metoprolol, in
Our study shows that diabetes, whether chronic or new
onset, increases mortality in patients with heart failure.
Further, we have shown that, in addition to a high baseline
prevalence of diabetes (24%), the incidence of diabetes is
substantial (a further 10–15%) among patients with heart
Blood glucose (mmol/l)
(Error bars represent 1 standard error)
without diabetes and treated with carvedilol and metoprolol. There was no
significant difference between patients treated with carvedilol and
metoprolol, but there was an overall significant trend for an increase in
random blood glucose over the course of the trial in patients without
diabetes at baseline (p,0.0001).
Values of random glucose measurements in patients with and
Percentage with end point
95% CI p value
0.82 0.71 to 0.94 0.006
Percentage with end point
95% CIp value
0.85 0.69 to 1.06 0.147
and without diabetes.
All-cause mortality in patients with
New onset diabetes: COMET971
failure during 5 years of follow-up, and among patients who
have not been diagnosed with diabetes, there is a progressive
increase in random blood glucose levels.
Diabetes is an important risk factor for the development of
cardiovascular disease, including heart failure,14and therefore
the high prevalence of diabetes in our study is not surprising.
The high risk of developing diabetes during the trial may reflect
a high prevalence of prediabetic glucose abnormalities at
baseline that developed into overt diabetes during the trial.
However, it is also possible that heart failure is a risk factor for
diabetes, rather than the opposite.15The gradual increase in
random glucose measurements over the course of the trial
should be interpreted similarly.
In 1996 Jacob et al demonstrated improved insulin sensitivity
when patients with hypertension were treated with carvedilol
and poorer insulin sensitivity during treatment with metopro-
lol.13This finding was the basis for a large hypertension trial in
patients with diabetes,9in which carvedilol stabilised HbA1c,
improved insulin resistance, and slowed development of
microalbuminuria, compared with metoprolol. The beneficial
effect of carvedilol on insulin sensitivity, compared with
metoprolol, is a possible explanation for the findings of the
present study, although the mechanism of this effect is
uncertain. However, both its a blocking and antioxidative
properties16may play a role. The antioxidative property might
be important for preserving b cells.17
Despite the adverse effect of b blockers on insulin sensitivity,
they appear effective in reducing major cardiovascular events
and death in patients with diabetes. A retrospective analysis
demonstrated reduced mortality in diabetic patients with
myocardial infarction when treated with b blockers,18and in
heart failure studies the benefit of b blockade was also evident
in the subgroup with diabetes.19 20Finally, the United Kingdom
Prospective Diabetes Study (UKPDS) demonstrated that b
blockade can prevent heart failure in patients with diabetes.21
In COMET, new onset diabetes was more likely to occur in
patients with concomitant cardiovascular risk factors (hyper-
tension, higher body mass index) and NYHA class IV, but less
likely to occur in the patients with NYHA class III and increased
serum creatinine levels. These last results contrast with those of
previous studies,5 15which showed a higher prevalence of
diabetes in the patients with more advanced heart failure.
Although we cannot explain the differences, we note that the
other studies examined prevalence, while we focused on
incidence in this study
The incidence of diabetes as well as that of diabetes related
adverse events is known to influence the outcome and resource
utilisation of the patients. It has been suggested that ACE
inhibitors and angiotensin receptor blockers reduce the
incidence of new onset diabetes compared with placebo in
randomised controlled trials.22As far as we know, our study is
the first trial showing that the choice of the b blocker can
influence the incidence of this event, with a lower rate of diabetic
related complications and new onset diabetes in patients assigned
to carvedilol than in those receiving metoprolol.
COMET has been criticised for the administration of doses of
metoprolol lower than in previous trials.23–25However, this
criticism is not applicable to the present study. The severity of
heart failure as judged by New York Heart Association class and
number of admissions to hospital was similar in the two
treatment groups,26and thus undertreatment of heart failure is
an unlikely explanation for the findings. It is doubtful that the
use of higher doses of metoprolol tartrate would have increased
the likelihood of developing new onset diabetes and diabetic
complications in this patient group.
There are some limitations to the study. This is a retrospective
analysis relying on post hoc identification of the end point of
new onset diabetes. A large proportion of patients in COMET
had ischaemic heart disease, and in such a population diabetes,
impaired glucose tolerance and insulin resistance are com-
mon.27It is therefore likely that the new onset diabetes in this
study is deterioration of pre-existing disturbances in glucose
The study relies on a definition of diabetes which is
essentially a clinical diagnosis and does not rely on formal
adherence to guidelines. This weakness is shared with most
other studies on the epidemiology of diabetes in heart failure.
This study demonstrates both a high prevalence and incidence
of diabetes in patients with heart failure over a course of 5 years
and a steady increase in random measurements of blood
glucose. New onset diabetes was more likely to occur during
treatment with metoprolol than during treatment with
The COMET study was sponsored by Hoffman-La Roche
Pharmaceuticals and GlaxoSmithKline Pharmaceuticals.
C Torp-Pedersen, Department of Cardiology, Bispebjerg University
Hospital, Copenhagen, Denmark
M Metra, Section of Cardiovascular Disease, Department of Experimental
and Applied Medicine, University of Brescia, Italy
A Charlesworth, P Spark, Nottingham Clinical Research Group (NCRG),
M A Lukas, GlaxoSmithKline, USA
P A Poole-Wilson, National Heart and Lung Institute, Imperial College
K Swedberg, Department of Medicine, Sahlgrenska University Hospital/
O¨stra, Go ¨teborg, Sweden
J G F Cleland, Department of Cardiology, University of Hull, Kingston upon
A Di Lenarda, Department of Cardiology, Ospedale di Cattinara, Trieste,
W J Remme, Sticares Cardiovascular Research Foundation, Rhoon,
A Scherhag, F Hoffmann - La Roche, Basel, Switzerland and I. Medical
Clinic, University Hospital Mannheim, University of Heidelberg, Germany
including both diabetes at baseline and new onset diabetes
as a time dependent factor. CAD removed, paced rhythm
added and CAD removed, AF added
Time dependent analysis of all-cause mortality,
RR (95% CI)p Value
Carvedilol v metoprolol
q Age (per year)
Female v male
q Weight (per kg)
Systolic BP .120 mm Hg
NYHA III v II
NYHA IV v II
q Duration of HF (per month)
q LVEF (per%)
q Haemoglobin (g/l)
q Sodium (mmol/l)
q Creatinine (mmol/l)
0.792 (0.698 to 0.899)
1.2 (1.046 to 1.377)
1.031 (1.023 to 1.038)
0.722 (0.603 to 0.863)
0.992 (0.987 to 0.997)
0.763 (0.667 to 0.873)
1.429 (1.246 to 1.639)
1.722 (1.294 to 2.293)
1.001 (1 to 1.002)
0.976 (0.967 to 0.985)
1.344 (1.167 to 1.548)
1.238 (0.997 to 1.538)
0.988 (0.835 to 1.169)
1.45 (1.263 to 1.666)
1.556 (1.308 to 1.851)
1.15 (1.003 to 1.318)
0.767 (0.647 to 0.908)
0.924 (0.885 to 0.965)
0.949 (0.933 to 0.965)
1.002 (1.001 to 1.003)
CAD, coronary artery disease; AF, atrial fibrillation.
972Torp-Pedersen, Metra, Charlesworth, et al
Competing interests: Andrew Charlesworth and Phillip Spark are employ- Download full-text
ees of Nottingham Clinical Research Group that performed the statistical
analyses of the trial. Mary Ann Lukas and Armin Scherhaug are employees
of the sponsors of the study. All other authors have competing interest in the
form of paid lectures and participation in advisory boards for numerous
The COMET investigators are listed in a previous publication: Poole-Wilson
PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and
metoprolol on clinical outcomes in patients with chronic heart failure in the
Carvedilol Or Metoprolol European Trial (COMET): randomised controlled
trial. Lancet 2003;362:7–13.
Ethical approval: This study was approved by all relevant ethical
committees before initiation.
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