ABSTRACT
Introduction:
Were the participants of the
EMPA-REG OUTCOME trial representative of
patients receiving empagliflozin in clinical
practice?
The aim of the present study was to
examine the prevalence of cardiovascular disease
(CVD) in type 2 diabetes patients starting
empagliflozin treatment in routine clinical
practice in Sweden.
Methods:
We used nationwide data from the
Swedish National Diabetes Register (NDR), the
Swedish Prescribed Drug Register, and the
Swedish National Patient Register to provide
clinical characteristics and ongoing treatments.
Results:
The total study cohort included
460,558 patients, of whom 130,508 (28.3%) had
a history of CVD. The number of patients
starting empagliflozin during the study period
was 16,985. Among these, 1952 (11.5%) had a
history of CVD. The patients starting empagliflozin
were younger than the total cohort and
were more likely to have retinopathy despite
having a similar duration of diabetes to the
overall cohort. They also exhibited higher BMI,
HbA1c, and eGFR, and were more likely to be
treated with insulin and lipid-lowering and
blood-pressure-lowering medications. The
patients with CVD who were starting empagliflozin
were slightly older and had been diabetic
for slightly longer than the patients without
CVD who were starting empagliflozin, but they
also had lower eGFR. Among the patients with
CVD who were starting empagliflozin, 87% had
coronary heart disease, 8% had suffered a
stroke, 13% had peripheral artery disease, 16%
had atrial fibrillation, and 20% had congestive
heart failure.
Conclusion:
The prevalence of CVD in patients
with type 2 diabetes in clinical practice in
Sweden was 28.3% during the study period, and
it was 11.5% in the patients starting empagliflozin
treatment. Patients of the latter cohort
were, however, younger, more obese, and more
likely to have unsatisfactory glycemic control,
requiring additional treatment. Overall, a large
proportion of type 2 diabetes patients should be
considered at high cardiovascular risk.
Björn Eliasson . Jan Ekelund . Rikard Amberntsson .
Mervete Miftaraj . Ann-Marie Svensson
From the article
INTRODUCTION
Persons with type 2 diabetes mellitus (T2DM)
are at elevated risk for premature death or
developing cardiovascular complications.
Although recent observational data show considerable
improvements in cardiovascular incidence
and mortality rates in persons with T2DM
between 1998 and 2013, these risks are still
clearly higher than in the general population
[1]. Cardiovascular disease (CVD) prevention
and management are thus essential parts of
diabetes care [2].
The EMPA-REG OUTCOME trial examined
the effects of empagliflozin, a sodium glucose
cotransporter-2 (SGLT-2) inhibitor, on cardiovascular
morbidity and mortality in patients
with type 2 diabetes at high risk for cardiovascular
events. The results showed reductions in
cardiovascular death, hospitalization from heart
failure, and all-cause mortality with empagliflozin
treatment on top of standard care (i.e.,
other treatments that lower glucose, blood
pressure, and blood lipids) as compared with
placebo [3].
Only patients with established cardiovascular
disease participated in the EMPA-REG OUTCOME
trial. Are these participants
representative of patients receiving empagliflozin
in clinical practice, and are the results
generalizable? Recently, a Swedish survey suggested
that the proportion of patients with type
2 diabetes (defined as being treated with any
glucose-lowering medication) in clinical practice
who had cardiovascular disease (coronary
heart disease, stroke, peripheral artery disease,
congestive heart failure, and atrial fibrillation)
was 34.2% in 2013, implying a clearly elevated
risk [4]. That study, however, lacked information
on clinical characteristics and risk factors.
The aim of the present study was to examine
the prevalence of CVD in patients with type 2
diabetes in routine clinical practice in Sweden—
applying a similar definition to that used in the
EMPA-REG OUTCOME trial—as well as the
prevalence of established CVD in patients who
were starting empagliflozin treatment. We used
nationwide data from the Swedish National
Diabetes Register (NDR) as well as the Swedish
Prescribed Drug Register and the Swedish
National Patient Register (National Board of
Health and Welfare) to probe clinical characteristics
and ongoing treatments.
DISCUSSION
This nationwide survey showed that patients
starting empagliflozin treatment were relatively
young compared with the overall cohort of
T2DM patients, and were generally more obese
and more likely to have unsatisfactory HbA1c
levels. In addition, retinopathy, micro- and
macroalbuminuria, and smoking were quite
common in the T2DM patients starting empagliflozin
treatment, in agreement with their
long mean duration of diabetes ([ 10 years).
Thus, a large proportion of the patients in this
nationwide cohort—even those with no history
of cardiovascular disease—would qualify as
high-risk individuals in recent major cardiovascular
outcome trials using SGLT-2 inhibitors
or GLP1-1 receptor agonists [8, 9].
In the multinational EMPA-REG OUTCOME
trial, 71% of the participants randomized to
empagliflozin treatment were male, and this
cohort presented the following mean values:
age 63.1 years, BMI 30.6 kg/m2 , HbA1c
65 mmol/mol, blood pressure 135.3/
76.6 mmHg, LDL cholesterol 2.2 mmol/l, and
eGFR 74.2 ml/min/1.73 m2 (MDRD) [3 ]. 48.0%
of the patients in the pooled empagliflozin
group were on insulin treatment, 94.9% were
on blood pressure-lowering treatment, and
81.5% were on blood lipid-lowering therapy.
Almost all of the patients in the empagliflozin
group had cardiovascular disease (99.4%),
75.6% had coronary heart disease, 23.1% had a
history of stroke, 21.0% had peripheral artery
disease, and 9.9% had congestive heart failure.
The Swedish patients with CVD who were
starting empagliflozin were quite similar to the
participants in the EMPA-REG OUTCOME trial.
The patients with no history of CVD were
younger, slightly more obese, and had higher
HbA1c, whereas the patients with a history of
CVD showed higher levels of coronary heart
disease and congestive heart failure but lower
levels of stroke and peripheral artery disease
than the participants in EMPA-REG OUTCOME.
A recent systematic review and meta-analysis
based on the results of the EMPA-REG OUTCOME
and DECLARE–TIMI 58 trials as well as
the CANVAS program recently concluded that
SGLT-2 inhibition should be considered in
patients with type 2 diabetes regardless of the
presence of atherosclerotic cardiovascular disease
or a history of heart failure, due to its
positive effects on glycemic control and the
risks of heart failure and renal disease progression
[9 ]. Cardiovascular benefits seem to be
more pronounced in patients with established
atherosclerotic cardiovascular disease, as most
clearly demonstrated by the EMPA-REG OUTCOME
trial [3 ]. The CANVAS program and the
DECLARE–TIMI 58 trial, which tested the safety
of canagliflozin and dapagliflozin, respectively,
had larger proportions of patients at elevated
cardiovascular risk, similar to the Swedish
cohort, but they did not have established CVD
[10 , 11 ]. This difference may have contributed
to the outcome differences between the three
trials.
The major strength of the present survey was
its nationwide scope and the high validity of
the data obtained, but one limitation of the
study is that we did not address other
comorbidities at baseline. We also used a crosssectional
design and did not follow the patients
longitudinally in this study. However, in a
recent observational cohort study of side effects
that used nationwide registers from Sweden and
Denmark, we found a numerically low but
increased risk of lower limb amputation and
diabetic ketoacidosis in patients using SGLT-2
inhibitors compared with those on GLP1
receptor agonists, but there were no other serious
adverse events of concern [12 ].
Other recent studies in general or high-risk
populations in clinical practice have also
investigated patients offered treatment with
empagliflozin or other SGLT-2 inhibitors and
the results of such treatment [13 –16 ]. In
essence, those studies have highlighted the
positive effects as well as the safety aspects of
this class of glucose-lowering medications.
These effects have been attributed to several
mechanisms, such as diuresis, natriuresis, and
their glucose-lowering, metabolic, and renal
effects [17 –19 ].
CONCLUSION
The prevalence of CVD in patients with type 2
diabetes in clinical practice in Sweden was
28.3% during the study period, and it was
11.5% in patients starting empagliflozin treatment.
Patients in the latter cohort were, however,
younger and more obese and had
unsatisfactory glycemic control, requiring
additional treatment. Overall, a large proportion
of T2DM patients should be considered at
high cardiovascular risk.
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