High risk of cardiovascular events was defined as the presence of ≥1 of the following: History of myocardial infarction >2 months prior to informed consent Evidence of multi-vessel coronary artery disease i.e. in ≥2 major coronary arteries or the left main coronary artery, documented by any of the following: – Presence of significant stenosis: ≥50% luminal narrowing during angiography (coronary or multi-slice computed tomography) – Previous revascularization (percutaneous transluminal coronary angioplasty ± stent or coronary artery bypass graft >2 months prior to consent – The combination of revascularization in one major coronary artery and significant stenosis (≥50% luminal narrowing) in another major coronary artery Evidence of single-vessel coronary artery disease, ≥50% luminal narrowing during angiography (coronary or multi-slice computed tomography) not subsequently successfully revascularized, with at least 1 of the following: – A positive non-invasive stress test for ischemia – Hospital discharge for unstable angina ≤12 months prior to consent Unstable angina >2 months prior to consent with evidence of single- or multi-vessel coronary artery disease History of stroke (ischemic or hemorrhagic) >2 months prior to consent Occlusive peripheral artery disease documented by any of the following: – Limb angioplasty, stenting, or bypass surgery – Limb or foot amputation due to circulatory insufficiency – Evidence of significant peripheral artery stenosis (>50% on angiography, or >50% or hemodynamically significant via non-invasive methods ) in 1 limb – Ankle brachial index <0.9 in ≥1 ankle
AE: 29.3 p 23.4 Refusal 7.4 5.1 Non-complance 0.6 0.6 Lost to f/u 0.6 .03 Lack of efficacy 0.5 <0.1
MI occurred in 4.8% patients in the empagliflozin and 5.4% in the placeo group, and stroke in 3.5% and 3.0% of patients, respectively
Empagliflozin and Cardiovascular Outcomes
U Y E N N G U Y E N
P H A R M D C A N D I D A T E 2 0 1 6
W E S T E R N N E W E N G L A N D U N I V E R S I T Y
C O L L E G E O F P H A R M A C Y
Outcomes, and Mortality in Type 2
There are 29.1 mil Americans (9.3% of the
population) with Type 2 Diabetes Mellitus (T2DM) in
Remains the 7th leading cause of mortality in the
United States in 20101.
Total costs of diagnosed DM is $245 billion in 2012
($176 billion for direct medical costs and $69 billion
in reduced productivity)1.
Hospitalization rates for MI and stroke were 1.8 times
and 1.5 times, respectively, higher among adults with
DM than those without.
Sodium-Glucose Cotransporter 2 (SGLT2)
SGLT2 receptors are expressed almost exlcusively
in the kidney and are responsible for the majority
of glucose reabsorption2.
Inhibition of SGLT2 can decrease plasma glucose
by increasing urinary glucose excretion2.
First agent, canagliflozin (Invokana®) became
available on the US market May, 2013.
Sodium-Glucose Cotransporter 2 (SGLT2)
Other agents: dapagliflozin, empagliflozin, and
Both canagliflozin and dapagliflozin are on the VA’s
Formulary status of empagliflozin is pending.
The drug monograph is available on PBM Intranet.
FDA-Approved SGLT2 Inhibitors for T2DM
Brand name Active ingredient(s)
Invokamet canagliflozin and metformin
Xigduo XR dapagliflozin and metformin
Glyxambi empagliflozin and linagliptin
Synjardy empagliflozin and metformin
List of fda-approved sglt2 inhibitors for type 2 diabetes. Available from http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm3
Review of Drug Class
The effects is independent of
insulin secretion by the
High cost (approx. $200+/month)
Mean reduction of HbA1c ≤1% Increased risks of UTIs, genital
mycotic infections, osmotic diuresis,
Weight loss FDA-warning about DKA (12/4/15)
that requires surveillance for 5 years
for all SGLT2 inhibitors3
Reduction in BP
Dosing: initial 10mg po once daily; may increase
to 25mg po once daily4.
Persistent eGFR <45: d/c therapy.
eGFR <30: use is contraindicated.
ESRD, dialysis: use is contraindicated.
Common Adverse Events: hypoglycemia, UTI,
increased LDL cholesterol (5-7%), dyslipidemia,
increased hematocrit (3-4%), increased risk of
Available from: http://media.breitbart.com/media/2015/09/ap_jardiance_ap-photo-wi-640x640.jpg
Zinman B, et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med; 2015 5
The presence of both T2DM and CV disease
increases the risk of death.
Evidence that glucose-lowering therapy reduces the
rates of CV events and death has not been
There is concern that intensive glucose lowering or
the use of specific glucose-lowering drugs may be
associated with adverse CV outcomes.
It is necessary to establish the CV safety benefits of
EMPA-REG OUTCOME TRIAL
The effects of empagliflozin in addition to standard
care, on cardiovascular morbidity and mortality in
patients with T2DM at high cardiovascular risk are
Hypothesis: to demonstrate noninferiority for the
primary outcome with empagliflozin versus placebo
with a margin of 1.3 for hazard ratio.
Designed and overseen by steering committee of
academic investigators and employees of
Phase III, multicenter, international, randomized,
double-blind, placebo-controlled trial.
Enrollment: September 2010 to April 2013.
Locations: 590 sites from 42 countries in North
America (plus Australia and New Zealand), Latin
America, Europe, Africa, and Asia.
Trial continued until an adjudicated primary
outcome event had occurred in at least 691 patients.
Patients who are:
≥ 18 years of age
eGFR of at least 30mL/min/1.73 m2 BSA
Had established cardiovascular disease
Had received no glucose-lowering agents for ≥12
weeks before randomization
Had HbA1c ≥ 7.0% and ≤ 9.0%
Definition of High Risk of Cardiovascular Events
(≥1 of the following)
H/o of MI >2mo prior to informed consent.
Evidence of multi-vessel CAD i.e. presence of
significant stenosis, prev revascularization, and/or
combination of the above.
Evidence of single-vessel CAD: ischemia, hospital
discharge for unstable angina ≤12 mo prior to consent.
H/o stroke >2 mo prior to consent.
Occlusive PAD: limb angioplasty, stenting,
bypass/amputation d/t circulatory insufficiency;
significant peripheral artery stenosis; ankle brachial
index <0.9 in ≥ 1 ankle.
Key Exclusion Criteria
Patients who have:
Uncontrolled hyperglycemia (glucose >240 mg/dL).
Liver disease (indicated by AST, ALT or alk
phosphatase >3x ULN).
Planned cardiac surgery or angioplasty within 3
Contraindications to background therapy according to
Any uncontrolled endocrine disorder except T2DM.
2-week, open-label, placebo run-in period with unchanged
background glucose-lowering therapy.
7020 patients randomly assigned in a 1:1:1 ratio to different
Empagliflozin N= 4687
10mg once daily N=2345
25mg once daily N=2342
Blocked randomization was stratified according to:
HbA1c at screening (< 8.5% or ≥8.5%)
BMI (<30 or ≥30)
Renal function (eGFR: 30-59 mL, 60-89 mL or ≥90 mL/min/1.73m2)
During first 12 weeks after randomization:
Background glucose-lowering therapy remained unchanged .
Intensification of therapy, dose reduction or discontinuation
of background medication were allowed if clinically
After week 12:
Investigators were encouraged to adjust glucose-lowering
therapy, and treat other CV risk factors at their discretion to
achieve best available standard of care according to local
Follow-up visits: at week 4, 8, 12, 16, 28, 40 and 52
after randomization and 30 days after completion
Primary outcome: composite of death from
cardiovascular causes, nonfatal MI (excluding silent
MI), or non fatal stroke.
Key secondary outcome: composite of the primary
outcome plus hospitalization for unstable angina.
Safety was assessed on the basis of adverse events
occurred during and 7 days after the last dose.
Key adverse events are:
Hypoglycemic events (plasma glucose ≤70mg/dL or events
Side effects: UTI, genital infection, volume depletion, acute
renal failure, bone fracture, DKA, and thromboembolic events.
Statistical model for primary analysis: Cox
proportional- hazards model with study group, age,
sex, baseline BMI, baseline HbA1c, baseline eGFR,
and geographic location as factors.
A two-sided P value of 0.0498 was considered to
indicate statistically significance.
Modified ITT was used as primary analysis among
patients who had received at least one dose of study
cardiovascular risk factors
use of glucose-lowering
use of statins/ezetimibe
use of anti-hypertensive
use of acetylsalicylic acid.
• Kaplan-Meier estimates were used to calculate cumulative
incidence for death from any cause.
• Subgroup analyses were performed in subgroups by
Patient Population/Baseline Characteristics
At baseline, demographic and clinical characteristics
are well-balanced between placebo and empagliflozin
Median age is 63.2
>70% are male and Caucasian
Average HbA1c is 8.08%
Over 50% of patients have T2DM for >10 years
Over 95% have CV risk factor (i.e: existing CAD, h/o MI, stroke,
PAD, cardiac failure…).
90% are on anti-hypertensive therapy (ACE/ARBs > 80%).
About 80% are on lipid-lowering therapy (>70% on statins)
>88% on anti-coagulants (~ 82.6% on acetylsalicylic acid)
Overall, 97% of patients completed the study, 25.4%
prematurely discontinued the study drug.
Reasons for premature discontinuation:
Refusal to continue, not due to adverse event
Lost to f/u
Lack of efficacy
Final status was available for 99.2% of all patients.
Median duration of treatment: 2.6 years.
Median observation time: 3.1 years.
Primary outcome: statistically significant lower risk of
death in study drug group-HR: 0.86; 95.02% CI:
0.74-0.99; P <0.001 for noninferiority and P=0.04 for
Key secondary outcome: statistically insignificant
between the two groups-HR: 0.89, 95%CI: 0.78-1.01;
P<0.001 for noninferiority and P=0.08 for superiority.
Results- Secondary Outcomes
• Empaglifozin group
significant lower risk
of death from CV
causes, death from
any cause, and
HF; for HF or death
from CV causes
excluding fatal stroke
than in the placebo
• No significant
differences in the
occurrence of MI or
No statistically significant differences in primary and
secondary outcomes for the 10-mg and 25-mg
groups versus placebo.
HR 0.85 (95% CI, 0.72-1.01; P=0.07) for the 10mg.
HR 0.86 (95% CI, 0.73-1.02; P=0.09) for the 25mg.
In subgroup analyses:
Consistent benefit of empagliflozin versus placebo on death
from CV causes across all subgroups.
Some heterogeneity for the primary outcome in age, and
Glycemic control after 12 weeks
Reduction of 0.54% points (95% CI, -0.58 to -0.49) in 10mg
Reduction of 0.60% points (95%CI, -0.64 to -0.55) in 25mg
Cardiovascular risk factors
Empagliflozin was associated with small reductions in weight,
waist circumference, uric acid level, and BP.
Small increase in LDL and HDL cholesterol observed in the
study drug group.
39 patients (41 in the 10-mg group and 38 in the 25-
mg group) would need to be treated during a 3-year
period to prevent 1 death.
Many patients did not reach their glycemic targets
At week 206, adjusted mean A1c for empagliflozin pooled
group is 7.81% and 8.16% for placebo group.
Similar side effect profile between the empagliflozin
group and placebo group.
Genital infection was reported in higher percentage of
patients in study drug group.
Urosepsis was reported in 0.4% patients in empagliflozin
versus 0.1% in placebo group.
No relevant changes in electrolytes between the groups.
Hematocrit values were higher in empagliflozin groups
than in placebo group:
Change from baseline in 10mg group: 4.8±5.5%
25mg group: 5.0 ±5.3%
Placebo: 0.9 ±4.7%
Patients with T2DM at high risk for cardiovascular
events who received empagliflozin had significantly
lower rates of the primary composite cardiovascular
outcome and of death from any cause than did those
in the placebo group when the study drugs were
added to standard care.
assessment study: Phase III randomized,
multicenter, double blind, placebo-controlled study-
Expected to conclude in 2017.
Purpose: to assess canagliflozin in the treatment of patients
with T2DM with regard to cardiovascular (CV) risk for major
adverse cardiac events (MACE). Other objectives include
evaluating the overall safety, tolerability, and effectiveness of
Multicenter trial to evaluate the effect of
dapagliflozin on the incidence of
cardiovascular events (DECLARE-TIMI58)-
randomized, double blind study- Expected to
conclude in 2019.
Purpose: To determine if dapagliflozin when added to a
patients current anti-diabetes therapy is effective in reducing
cardiovascular events such as myocardial infarction (MI)
(heart attack), ischemic stroke, and cardiovascular (CV)
related death, compared with placebo (inactive study
Baseline characteristics are
similar among all patients.
Similar use of medications
to manage other health
Majority are male, and
All with existing CVD risk
Not adequate information
available for adverse events
of the study drug
Many patients did not
reach their glycemic targets
Results cannot be extrapolated to patient
populations with other clinical characteristics.
Risk-benefit profile was not discussed.
May prove that the risk of cardiovascular death in
patients with T2DM and cardiovascular disease can
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Diabetes Association. Available from: https://professional.diabetes.org/facts.
2. Andrianesis V, Doupis J. The role of kidney in glucose homeostasis- sglt2 inhibitors,
a new approach in diabetes treatment. Expert Rev Clin Pharmacol. 2013; 6(5): 519-
3. Fda drug safety communication: fda revises labels of sglt2 inhibitors for diabetes to
include warnings about too much acid in the blood and serious urinary tract
infections [Internet]. Silver Spring (MD): US Food and Drug Administration; 2015
[cited 2015 Dec 9]. Available from:
4. Empagliflozin. In: Lexi-Drugs [database on the Internet].Hudson (OH): Lexi-Comp,
Inc.; 2007 [cited 2015 Dec 9].
5. Bernad Z, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and
mortality in type 2 diabetes. N Engl J Med. 2015; 373: 2117-2128.
6. Canvas-canagliflozin cardiovascular assessment study. Bethesda, MD: US National
Institutes of Health. Available from: https://clinicaltrials.gov/show/NCT01032629.
7. Multicenter trial to evaluate the effect of dapagliflozin on the incidence of
cardiovascular events (declare-timi58). Bethesda, MD: US National Institutes of
Health. Available from: