Practice Update: Diabetes

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SGLT2 Inhibitors are Associated with Reduced Cardiovascular
Disease in Patients with Type 2 Diabetes
The new medication class, sodium-glucose transporter-2 (SGLT2) inhibitors, has been associated with lower
rates of death and hospitalization for heart failure in patients with type 2 diabetes, both with and without existing
cardiovascular disease, and regardless of the specific SGLT2 inhibitor used.
This outcome of the population-based
Hospitalization for Heart Failure and
Death inNewUsers of SGLT2 Inhibitors
in Patients With and Without Cardiovascular
Disease (CVD-REAL) trial was reported at This
outcome of the international phase 3, rand-
omized, double-blind, placebo-controlled
ODYSSEY-DM Insulin Trial was reported at
the American Diabetes Association’s 77th
Scientific Sessions, from June 9–13.
Matthew A. Cavender, MD, MPH, of the
University of North Carolina School of Med-
icine in Chapel Hill, explained that SGLT2
is a protein responsible for glucose regula-
tion. SGLT2 inhibitors reduce renal glucose
reabsorption by causing excess blood glu-
cose to be expelled through urine.
The CVD-REAL study analyzed outcomes of
306,156 patients with type 2 diabetes from
the US, UK, Norway, Sweden, and Denmark
who were treated with SGLT2 inhibitors.
Using data from clinical practice, Dr Cav-
ender and colleagues compared rates of
heart failure and death in patients with
and without prior cardiovascular disease
vs heart failure rates in new users of SGLT2
inhibitors and other glucose-lowering
drugs. Data on heart failure and subse-
quent death rates were collected using
medical records, medical claims, electronic
health records, and national registers.
Propensity scores were used to match
patients treated with SGLT2 inhibitors
and other glucose-lowering drugs. After
matching, baseline characteristics were
balanced between groups, and 306,156
patients, >150,000 person years (100,947
person years for SGLT2 inhibitors; 89,208
person years for other glucose-lowering
drugs) and 950 new heart failure events
were analyzed. Hazard ratios for heart fail-
ure, death, and the composite of death or
heart failure were estimated by country and
pooled as a weighted average.
An association between SGLT2 inhibitors
and lower rates of death due to heart fail-
ure and hospitalization for heart failure was
seen in all five participating countries. Fur-
thermore, the benefits of SGLT2 inhibitor
treatments were consistent regardless of
the type of SGLT2 inhibitor used, which var-
ied from country to country.
SGLT2 inhibitors vs other glucose-lowering
drugs were associated with 31% lower rates
of heart failure in patients with existing and
45% without existing cardiovascular dis-
ease (hazard ratio 0.69, 95% confidence
interval 0.59–0.80; hazard ratio 0.55, 95%
confidence interval 0.34–0.88).
Similar results were seen for death and death
due to heart failure regardless of whether
patients had a history of cardiovascular
disease. All patients treatedwith SGLT2 inhib-
itors were less likely to suffer heart failure or
subsequent death vs patients receiving other
glucose-lowering drugs.
Dr Cavender concluded, “Results of this
study offer further evidence regarding the
potential of SGLT2 inhibitors to improve
outcomes in patients with diabetes. While
our results were striking in their similar-
ity to a prior randomized study evaluating
the benefit of SGLT2 inhibitors in patients
with diabetes and known cardiovascular
disease, the results went one step further
to show that SGLT2 inhibition may benefit
patients with diabetes regardless of whether
they harbor known cardiovascular disease.
It is also important to note the significant
difference in the particular SGLT2-inhib-
itor used in each country. This difference
suggested that benefits seen with SGLT2
inhibitors were likely a class effect. Research
has shown that patients with diabetes are at
30% higher risk of heart failure vs patients
without diabetes. These findings suggested
that use of SGLT2 inhibitors may provide
the opportunity to reduce the incidence of
heart failure among patients with diabetes.”
Ongoing randomized clinical trials with
SGLT2 inhibitors are likely to provide con-
siderable additional information regarding
their clinical effectiveness. As a follow-up to
this study, the effectiveness of SGLT2 inhib-
itors on other important clinical events are
being further evaluated. Such evaluation will
broaden the study’s focus on associations
between other drugs for patients with diabe-
tes and a history of cardiovascular events.
PracticeUpdate Editorial team.
Dr Leiter presented results of patients with
type 2 diabetes (n = 441, LDL-C ≥70 mg/dL
(1.81 mmoL/L). They were taking either tak-
ing the maximum tolerated statin dose or
were unable to tolerate any statin. Addi-
tionally, they harbored atherosclerotic
cardiovascular disease or at least one
other cardiovascular risk factor.
Patients were randomized to either an
injection of 75 mg of alirocumab (n = 294)
or placebo (n = 147) injection once every 2
weeks. Patients in the alirocumab group
whose LDL-C was ≥70 mg/dL at 8 weeks
received a blinded dose increase to 150
mg at week 12.
Primary endpoints were the difference
between treatment arms in percentage
change of calculated LDL-C from baseline
to week 24 and adverse events.
At 24-weeks, alirocumab reduced LDL-C
significantly, by 49% vs placebo and
improved other lipid parameters as well.
Further, 80% of patients reached rec-
ommended target LDL-C levels with
alirocumab 75 mg.
Dr Leiter concluded that co-administration
of alirocumab and insulin was safe and the
incidence of adverse events was generally
similar between alirocumab and placebo.
Additionally, alirocumab was well tolerated
and did not affect glucose control. Results
were comparable to those seen in previ-
ous ODYSSEY trials.
This study also evaluated the effect of ali-
rocumab on some newer lipid parameters
that will enable a better understanding of
the effect of alirocumab on atherogenic
diabetic dyslipidemia. Atherogenic diabetic
dyslipidemia is caused by insulin resist-
ance primarily, and is characterized by high
serum triglycerides, elevated LDL levels,
low HDL levels, and postprandial lipemia.
Dr Leiter concluded, “Results of the ODYS-
SEY DM-Insulin study provided valuable
information on the efficacy and safety of
alirocumab in this high cardiovascular risk
group and will help guide clinical deci-
sion-making beyond statin therapy.”
Results on the efficacy and safety of aliro-
cumab in patients with type 1 diabetes will
be reported at a later date.
PracticeUpdate Editorial team.
ADA 2017 9
VOL. 1 • NO. 2 • 2017