only red flags so far raised about the
gliflozins class of drugs is a potential
for volume depletion-related adverse
events and a concern that they may
increase the risk of diabetic ketoacidosis (DKA).
In a warning released in May
2015, the U.S. Food and Drug Administration (FDA) said that patients
should be aware of the symptoms of
DKA (“difficulty breathing, nausea,
vomiting, abdominal pain, confusion,
and unusual fatigue or sleepiness”)
and seek medical attention immediately if they occur. The tricky part
for these patients hinges on the fact
that they don’t feel well but because
their blood glucose stays in a normal
range, they don’t seek attention.
“We have to learn to recognize
this known complication of diabetes
and be ready to find it when a welltreated type 2 diabetic comes in feeling poorly, maybe a bit of abdominal
discomfort, and their blood sugar
might be 160, but their bicarbonate
is 16 and they are actually breathing a little bit Kussmaulian, so that’s
the circumstance when we check
the urine and maybe the blood for
ketones,” said Raymond Townsend,
MD, PhD, University of Pennsylvania, Philadelphia, PA, in an on-camera interview with CSWN.
Empagliflozin is actually the
third SGLT2 inhibitor to receive FDA
approval, preceded by canagliflozin
(Invokana, Janssen Pharmaceuticals) and dapagliflozin (Farxiga,
AstraZeneca/BMS). All three are
undergoing rigorous testing of their
CV outcomes (TABLE 1) as is a fourth
in class agent, ertugliflozin (Merck
Sharp & Dome Corp/Pfizer), not yet
FDA approved. Although it’s unclear
if the findings from EMPA-REG OUTCOME represent a class effect, there
is promising evidence from a recent
meta-analysis.10
By the way, there are nine
FDA-approved classes of pharmacotherapy for T2DM (TABLE 2). Trying
to ascertain cardiac risk of these has
proven challenging. In the case of the
glitizones, for example, for several
years the FDA released a number of
advisories, which were subsequently
removed. A 2014 meta-analysis
found no suggestion of CV harm (or
benefit) with the gliptins.12
Obesity: The Weight of the
World
You may have noticed: no CVD
risk prediction score includes body
ACC.org/CSWN
weight. General obesity is not an
independent risk factor and does
not improve CVD risk prediction in
women or men. In support of this
perhaps surprising point: CVD mortality has continued to fall despite
a robust obesity epidemic in which
74% of men and 64% of women are
now overweight/obese, and obesity
reduction trials have failed to reduce
CVD. So, is obesity another elephant
or a red herring?
In the last year, investigators have
reported on the potential role of obesity in atrial fibrillation, which—it
is fair to say—has reached epidemic
proportions, too. At the end of 2015,
the Journal of the American College
of Cardiology published a review of
emerging data on the importance
of weight loss and cardiovascular
exercise in the prevention and management of AF.13 The authors noted,
“Currently, the body of evidence
is enough to strongly recommend
weight loss for both prevention and
management of AF.” (Obesity joins
the list of modifiable risk factors for
AF, listed in TABLE 3.)
In a study of more than 8,000
people followed for almost a decade,
Vermond et al. identified
obesity as a significant risk
factor for incident AF, with a
45% increased risk for every
5 kg/m2 increase in body
mass index.14 Animal studies
suggest that obesity directly
contributes to the AF substrate
by altering atrial electrical and
structural remodeling. Obesity
also could increase the risk
of AF by its association with
other risk factors, including
epicardial fat, which has been
identified as a risk factor
for the increased prevalence
and severity of AF, perhaps
because it is metabolically active and
produces inflammatory cytokines.
Similarly, patients with obstructive sleep apnea (OSA) have roughly
a 4-fold increased risk of developing
AF.15 It is not yet clear whether OSA
is a causal risk factor or part of a
larger risk profile, but the finding
that continuous positive pressure
ventilation reduces the recurrence
rates of AF in these patients suggests
a possible pathogenic role.
In an accompanying commentary
to the Vermond study, Kowey and
To watch an interview with Raymond
Townsend, MD, PhD, and Katherine
Merton, PhD, MBA, on New Agent
Targets Type 2 Diabetes and Hypertension, scan the QR code.
To watch an interview with Yashashwi Pokharel, MD, on Frequency
and Practice Level Variation in Statin
Use Among Patients with Diabetes,
scan the QR code.
To view an interview with Rajeev K.
Pathak, MBBS, and Prashanthan
Sanders, MBBS, PhD, on the LEGACY
of Sustained Weight Loss: Reduction
of AF Burden, scan the QR code.
Robinson found a ray of hope in the
midst of the obesity and AF epidemics.16 Studies have demonstrated that
physician-led weight loss programs
can significantly reduce the number
of AF episodes, as well as the symptom burden and severity in obese
patients with AF. They wrote, “Such
studies indicate that the medical
community will likely need to take a
much more active role in facilitating
risk factor modification to slow the
rising incidence of AF globally.”
It’s not just an issue of weight:
TABLE 1. Ongoing CV Outcome Trials with SGLT-2 Inhibitors
Trial
N
Drug
Population
Primary Outcome
CANVAS
4,330
Canagliflozin vs. placebo
T2DM with Hx atherosclerosis
CV death, nonfatal MI, stoke
CANVAS-R
>5,800
Canagliflozin
T2DM with Hx or risk of
CVD
Progression of albuminuria
DECLARE-TIMI 58
17,150
Dapagliflozin vs. placebo
T2DM + CVD or CVD risk
CV death, MI, stroke
CREDENCE
4,200
Empagliflozin vs. placebo
T2DM, stage 2 or 3 CKD on
maximum ACE/ARB
ESKD, renal and vascular outcomes of canagliflozin vs. placebo
VERTIS
3,900
Ertugliflozin vs. placebo
T2DM + CVD
CV death, MI, stroke
ACE/ARB = angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; CV = cardiovascular; CVD = cardiovascular disease; ESKD = endstage kidney disease; Hx = history; MI = myocardial infarction; T2DM = type 2 diabetes mellitus. (Adapted and updated from Lathief and Inzucchi.11)
Approved Classes of Drugs for
Treating Type 2 Diabetes
TABLE 2.
TABLE 3. AF Risk Factors
Modifiable
Metformin
Obesity
Sulfonylureas (chlorpropamide, glyburide, glipizide, and
glimepiride)
Hypertension
Meglitinides (rep