That’s all pretty broadly known
among the cardiovascular community.
But in the last couple years, some confusion has set in. It stands to reason
that tight glucose control should reduce
risk and including glycemic measures
in algorithms used to calculate risk of
CVD might improve their predictive
ability. Indeed, guidelines on risk assessment conclude that measurement
of glycoslated hemoglobin or HbA1c
levels may be reasonable in asymptomatic adults without a diagnosis of diabetes. Makes sense…until you look at
the data. It turns out that HbA1c is not
associated with clinically meaningful
improvement in assessment of CVD
risk. That was a big surprise when
the results were first reported of an
analysis of data from almost 300,000
people without known diabetes and
CVD at baseline indicates.7
There seems to be a glucose
paradox: while fasting blood sugar
and HbA1c predict future macro- and
microvascular events, tight glucose
control definitely reduces microvascular events but does not impact
macrovascular effects. That’s quite
different from blood pressure control
and the use of statins for lipid lowering, both of which reduce macrovascular events. So, does a place for tight
glucose control exist? Probably.
Dr. Creager and colleagues note
that, despite this paradox, diabetes
is most certainly a risk multiplier in
atherosclerosis. It increases both the
risk of developing atherosclerosis
and the incidence of complications of
atherosclerosis, and is associated with
poorer outcomes from these events.
They added that health care professionals enjoy the benefit of a wide
variety of clinical trial data supporting specific treatments and targets for
patients with diabetes. These include:
• Lipid-lowering therapy with
statins, medication for blood
pressure control, and antiplatelet
therapy in patients with increased
cardiovascular risk scores.
• Hyperglycemia should be
treated to a target glycosylated
hemoglobin of 7%, with therapy
that includes an agent that improves insulin sensitivity, such
as metformin.
• Optimal medical treatment,
including risk factor modification, antiplatelet therapy, and
antianginal medications re-
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CardioSource WorldNews
mains the preferred approach
for most patients wit h diabetes
and stable CAD.
What about aggressive glucoselowering therapy? When you parse
the data, this approach continues
to demonstrate benefits in some
individuals. At ACC.15, Dr. Creager
said aggressive glucose lowering is
particularly warranted in younger,
leaner patients with a shorter duration of T2DM, lower baseline HbA1c
levels, and without evident CAD.
While tight glycemic control
improves macrovascular events, caution is warranted in older patients
and those with established CVD
or multiple comorbidities. He also
emphasized that aggressive early
treatment of T2DM may impact CV
events due to a legacy, or memory,
effect which may take many years to
become evident.
“A Heart Med Masquerading
as a Diabetes Med”
At a scientific meeting, a presenter
will commonly enjoy polite applause
upon reaching the end of his or her
presentation. But it’s not often the
findings of a new trial are met with
a gasp followed immediately by a
standing ovation. When it happens,
it’s a good guess the findings might be
“game changing.”
Enter the EMPA-REG OUTCOME
trial.
“It’s the first rigorously designed,
positive clinical outcomes trial using
any clinical outcome endpoint in
the field of diabetes, type 1 or type
2,” said Darren K. McGuire, MD,
MHSc, in an interview with CardioSource WorldNews. “It is absolutely a
game-changing result.”
Dr. McGuire is the Dallas Heart
Ball Chair for Research on Heart
Disease in Women at UT-Southwestern Medical Center in Dallas, and
an expert in large-scale clinical trial
design and execution. He is the coeditor of Diabetes in Cardiovascular
Disease: A Companion to Braunwald’s
Heart Disease (1st edition, 2015)
and disclosed that he consults with
several pharmaceutical companies on
their diabetes programs.
With nearly 1 in 10 U.S. adults
suffering from type 2 diabetes, it’s no
wonder the EMPA-REG OUTCOME
trial results engendered excitement
from diabetologists. The results
were initially presented at the 2105
European Association for the Study
“[The EMPA-REG OUTCOME trial is] the first
rigorously designed, positive clinical outcomes
trial using any clinical outcome endpoint
in the field of diabetes, type 1 or type 2. It is
absolutely a game-changing result.”
—Darren K. McGuire, MD, MHSc
of Diabetes meeting in September
with the main findings presented for
a cardio-centric audience at the 2015
AHA Scientific Sessions 2 months
later in Orlando.8
The trial enrolled patients with
T2DM and established CVD at high risk
for CV events and assigned to either
empagliflozin 10 or 25 mg (Jardiance,
Boehringer Ingelheim) or placebo. A total of 7,020 patients from 42 countries
and 590 sites participated.
Here’s why cardiologists should be
interested in this drug: over a median
of 3.1 years, empagliflozin (pooled
data from the doses studied) was
superior to placebo for the primary
composite outcome of CV death, nonfatal MI, or nonfatal stroke (10.5%
vs. 12.1%; hazard ratio [HR]: 0.86;
p = 0.04), with the difference driven
primarily by a 38% relative risk reduction (RRR) in CV death (p < 0.0001).
No significant differences were seen
in nonfatal MI or nonfatal stroke.
Empagliflozin also reduced the
composite of heart failure (HF) hospitalization and CV death (HR: 0.66; p <
0.001), with similar benefit seen with
both doses. All-cause hospitalization
was reduced by 11% with empagliflozin (HR: 0.89; p < 0.05).
Further investigation of HF outcomes in EMPA-REG were published
in January 2016 and showed that the
drug improved HF outcomes both
in those patients with and without
baseline HF.9
“We now have a drug that’s
labeled as a drug for diabetes that
actually prevents hospitalization for
heart failure and cardiovascular and
all-cause mortality, but none of us
believe (that) has anything to do with
blood glucose control, so it’s kind of
difficult to call this a diabetes drug,”
said Dr. McGuire. “It looks more like
it’s a cardiovascular drug that has a
side effect of lowering blood glucose.”
It Works, Use it!
As for Dr. McGuire, he started prescribing empagliflozin to his T2DM
patients the day after he saw the
EMPA-REG findings. “Despite my
diabetes interest, I have never managed blood glucose as a clinician, but
after EMAP-REG OUTCOME, it is the
first time in my career where I have
a drug that lowers blood glucose and
has cardiovascular risk benefit so I
use it not for the glucose benefit but
for the cardiovascular risk benefit.”
He lets his patients’ primary care
physicians know he has prescribed
an SLGT2 inhibitor, but doesn’t
delay starting the medication. “It’s
a simple prescription, there is no
dose titration and very little risk of
hypoglycemia. The two doses in the
trial looked identical, so I use 10 mg
daily and don’t think there is any
use for 25 mg.” His bigger concern
is affordability, since empagliflozin
costs about $300 monthly.
“Some physicians are still going
to wait and my question is what
are you waiting for? Do you think
there’s going to be another trial? No
way, we’ve got a winner here. The
trial was robust and well conducted;
the results were significant and
heart failure and CV death signals
were extremely robust.”
Most of the glucose filtered by
the kidneys is reclaimed in the proximal tubules and sodium glucose
cotransporter-2 (SGLT2) is responsible for about 90% of this reabsorption. A selective inhibitor of SGLT2,
empagliflozin reduces this reabsorption and increases urinary glucose
excretion. It is this “glucosuria” that
is responsible for the most common
known issue of SGLT2 inhibitors:
genital infections.
Other than glucosuria and an
increased risk of subsequent genital
infection, particularly in women, the
March 2016