18 / 24
Sulfonylureas are associated with increased
risks of cardiovascular events and death
Diabetes Care
Take-home message
•
This meta-regression analysis
included 19 studies investigating the
association between sulfonylureas
and cardiovascular events or mor-
tality, identifying 36 relative risks. Of
these relative risks, metformin was
the comparator in 75% and death
was the outcome in 67%. The rel-
ative risk was 13% higher when the
comparator was metformin, 20%
higher when death was the out-
come, and 7% higher when a study
design-related bias was present.
•
These results find that sulfonylureas
are associated with increased car-
diovascular and mortality risk in the
majority of studies without major
design-related bias, highlighting
the importance of the use of appro-
priate design and analytical tools
for accurate cardiovascular safety
assessments.
Abstract
Recent randomized trials have compared
the newer antidiabetic agents to treatments
involving sulfonylureas, drugs associated with
increased cardiovascular risks and mortality
in some observational studies with conflicting
results. We reviewed the methodology of these
observational studies by searching MEDLINE
from inception to December 2015 for all studies
of the association between sulfonylureas and
cardiovascular events or mortality. Each study
was appraised with respect to the comparator,
the outcome, and study design-related sources
of bias. A meta-regression analysis was used
to evaluate heterogeneity. A total of 19 stud-
ies were identified, of which six had no major
design-related biases. Sulfonylureas were asso-
ciated with an increased risk of cardiovascular
events and mortality in five of these studies
(relative risks 1.16–1.55). Overall, the 19 studies
resulted in 36 relative risks as some studies
assessed multiple outcomes or comparators.
Of the 36 analyses, metformin was the com-
parator in 27 (75%) and death was the outcome
in 24 (67%). The relative risk was higher by 13%
when the comparator was metformin, by 20%
when death was the outcome, and by 7% when
the studies had design-related biases. The low-
est predicted relative risk was for studies with
no major bias, comparator other than metformin,
and cardiovascular outcome (1.06 [95% CI 0.92–
1.23]), whereas the highest was for studies with
bias, metformin comparator, and mortality out-
come (1.53 [95% CI 1.43–1.65]). In summary,
sulfonylureas were associated with an increased
risk of cardiovascular events and mortality in the
majority of studies with no major design-related
biases. Among studies with important biases,
the association varied significantly with respect
to the comparator, the outcome, and the type
of bias. With the introduction of new antidia-
betic drugs, the use of appropriate design and
analytical tools will provide their more accurate
cardiovascular safety assessment in the real-
world setting.
Sulfonylureas and the risks of cardiovas-
cular events and death: a methodological
meta-regression analysis of the observational
studies.
Diabetes Care
2017 May 01;40(5)706-
714, L Azoulay, S Suissa.
COMMENT
By Peter Lin
MD, CCFP
A
fter the cardiovascular issues
with rosiglitazone, cardiovascular
safety trials had to be conducted
for all new antihyperglycemic agents.
However, approval for older medica-
tions was based simply on evidence of a
reduction in glucose parameters; cardio-
vascular safety was not a concern back
then.
Having said that, data from the UKPDS
trial shows that metformin reduces CV
events;
1
so, it was never in doubt. The
ORIGIN trial has shown no increased
harm with early initiation of insulin.
2
However, some questions linger regard-
ing the cardiovascular safety profile of
sulfonylureas. Data exist on the weight
gain and risk of hypoglycemia associated
with sulfonylureas, but the associated
cardiovascular events have not been
well-quantified. Sulfonylureas are used
commonly across the world and are very
effective in lowering HbA1C, but often the
effect wears off, as shown in the ADOPT
study.
3
This paper reviewed over 19 trials look-
ing at sulfonylureas, specifically studying
cardiovascular events and mortality. The
problem with some studies is that they
don’t take into account the duration of
diabetes et cetera; so, they may end up
comparing sicker patients with those
who aren’t as sick. This group looked at
potential biases such as exposure mis-
classification, time-lag bias, and selection
bias, and, of the 19 studies, 6 did not have
any of these biases. Of those 6 stud-
ies, 5 showed that sulfonylureas were
associated with an increased risk of car-
diovascular events and mortality, with
relative risks ranging from 1.16 to 1.55.
It is not possible to tease out what the
cause of the increase in events is based
on this type of analysis. Is it hypoglyce-
mia? Is it a direct drug effect? However,
regardless of the mechanism, the consist-
ent finding of increased cardiovascular
risk may have an impact on selection of
agents for our patients. Newer agents
have been shown not to increase
events, and recently some have even
shown reduction in events. So, perhaps
our algorithm of selecting medications
for our patients may have to change to
focus on the cardiovascular effects first
and then the glycemic benefits because,
in the end, our goal is preventing cardi-
ovascular events from happening in our
patients with diabetes.
References
1. UK Prospective Diabetes Study (UKPDS)
Group. Lancet 1998;352(9131):837-853.
2. The ORIGIN Trial Investigators. N Engl J Med.
2012;367(4):319-328.
3. Kahn SE, Haffner SM, Heise MA, et al. N Engl J
Med. 2006;355(23):2427-2443.
Dr Lin is Director of Primary
Care Initiatives, Canadian
Heart Research Centre,
and Medical Director of
LinCorp Medical Inc.
Perhaps our algorithm of
selecting medications for our
patients may have to change
to focus on the
cardiovascular effects first
and then the glycemic
benefits because, in the end,
our goal is preventing
cardiovascular events from
happening in our patients
with diabetes.
CARDIOVASCULAR COMPLICATIONS
18
PRACTICEUPDATE DIABETES