Empagliflozin in Prevention of Cardiovascular Disease among Patients with Diabetes Mellitus Type 2

Rose Jung, PharmD, MPH, BCPS

University of Toledo

Background
1. Cardiovascular disease risk in diabetes type 2 patients
a. Risk of coronary artery disease (CAD) is two- to four-fold higher among patients with T2DM1
b. Death from cardiovascular diseases (CVD) is two-fold higher among adults with Diabetes Mellitus type 2 (T2DM) and
life expectancy is reduced by 5-10 years1
c. Myocardial infarction (MI) accounts for 60% of deaths among patients with T2DM1
d. Risk for myocardial infarction (MI) [20%] and death from cardiovascular (CV) causes [15%] in patients with diabetes
mellitus type 2 (T2DM) without prior history of MI was same as patients without T2DM with prior history of MI2
e. Diabetes is associated with 2-fold increase in risk of heart failure in men and 5-fold higher risk in women3
2. FDA guidance based on evaluation of CV risk with new antidiabetic agents4
a. Need an independent CV end points committee for a prospective, blinded adjudication of CV events during all phase 2
and phase 3 trials
b. Include patients at higher risk of adverse CV events (e.g., advanced disease, elderly, impaired renal function)
c. Evaluate major adverse CV events (MACE) include CV death, MI, stroke and other endpoints of interest include
hospitalization for acute coronary syndrome, urgent revascularization procedures
d. If upper bound of the two-sided 95% CI is between 1.3 and 1.8, a post-approval CV outcome trail generally will be
required to definitively rule out a a30% excess risk of adverse CV events
e. If upper bound of the two-sided 95% CI is less than 1.3, a post-approval CV outcome trial may not be always necessary
3. Potential mechanisms for CV benefit5
a. Combined hemodynamic effects of reducing blood pressure, reducing aortic stiffness, and promoting intravascular
volume depletion
i. Peripheral vascular actions to reduce cardiac pre- and afterload and lower systolic blood pressure, providing
an important alleviation of cardiac stress
ii. Improved cardiac metabolism, enhancing diastolic and systolic function
iii. Diuresis leading to reduced extracellular fluid volume (reflected in a rise in haematocrit) and cardiac pre-load,
an action similar to that obtained with conventional diuretics
4. Previous studies
a. Canagliflozin Cardiovascular Assessment Study (CANVAS) 6
i. A RCT compared CV outcomes of canagliflozin to placebo in treating patients with T2DM with high CV risk.
ii. A total of 10,142 patients were randomized to receive canagliflozin 300 mg daily, canagliflozin 100mg daily, or
placebo and followed for 3.6 years.
iii. The mean age was 63 years, 36% were women, the mean duration of diabetes was 14 years with HgA1C of
8.2%, 66% had a history of cardiovascular disease, and 2% had amputations.
iv. Patients receiving canagliflozin had 14% relative reduction in composite outcome of death from CV causes,
nonfatal MI, or nonfatal stroke [HR, 0.86 (95% CI, 0.75-0.97); P<0.001 for noninferiority and p=0.02 for
superiority]. Hospitalization for heart failure [HR, 0.67 (95%CI, 0.52-0.87)], progression of albuminuria [HR,
0.73 (95%CI, 0.67-0.79)], and 40% reduction in eGFR, renal replacement therapy, or renal death [HR, 0.6
(95%CI, 0.47-0.77)] were significantly reduced in canagliflozin group. There was no statistical difference in any
individual components of primary objective.
v. Adverse events that was higher in canagliflozin group included genital infections, osmotic diuresis, and volume
depletion. Surprisingly, amputation was higher in canagliflozin group [6.3% in canagliflozin vs. 3.4% in
placebo; p<0.001).
vi. Limitations included higher HgbA1C (mean 8.2%) and lower prevalence of cardiovascular disease (66%)
b. Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER)Trial7
i. A RCT compared the CV outcome of liraglutide to placebo in treating patients with T2DM.
ii. A total of 9340 patients were randomized to receive liraglutide 1.8 mg or a placebo injection once daily in
addition to standard care and followed for 3.8 years.
iii. The mean age was 64 years, 65% were men, the mean duration of diabetes was 13 years with mean HgA1C of
8.7%, 81% had established CVD, 25% had chronic kidney disease of stage 3 or higher.
iv. Patients in liraglutide group showed 13% relative risk reduction in composite outcome of death from
cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke than those in placebo group (HR=
0.87, 95% CI= 0.78-0.97, p-value <0.001 for noninferiority, p-value= 0.01 for superiority). Death from CV

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 causes [HR, 0.78(95% CI, 0.66-0.93)] and death from any cause [HR 0.85 (95% CI, 0.74-0.97)] were significantly
lower in liraglutide group. There was no statistical difference in nonfatal MI, nonfatal stroke, or
hospitalization for heart failure.
v. Adverse events that were higher in the liraglutide group included acute gallstone disease, injection-site
reactions, nausea, vomiting diarrhea, abdominal discomfort, decrease appetite,
vi. Limitations included higher HgbA1C (mean 8.7%) and lower prevalence of cardiovascular disease (72.4%)
c. Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes
(SUSTAIN-6)8
i. A RCT compared the CV effects of semaglutide to placebo in patients with T2DM.
ii. A total of 3297 patients were randomized to semagludie 0.5mg or 1mg once weekly or placebo for median of
2.1 years.
iii. The mean age was 65 years, 60% were men, mean duration of T2Dm was 14 years with HgA1C of 8.7%, and
83% had CVD.
iv. The patients receiving semaglutide had 26% relative reduction in primary composite of CV death, nonfatal MI,
or nonfatal stroke compared to the placebo group [HR, 0.74 (95% CI, 0.58-0.95); p<0.001 for noninferiority].
There was slight reduction in nonfatal stroke, revascularization, retinopathy complication, and new or
worsening nephropathy.
v. Abdominal discomfort was the most frequent adverse event reported with semaglutide and resulted in more
frequent treatment discontinuation. Antibody to semaglutide formed in 30 patients.
vi. The limitations included smaller sample size, shorter duration of follow-up, and higher HgA1C.

References
1. Morrish NJ, Wang SL, Stevens LK, et al. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in
Diabetes. Diabetologia. 2001;44:S14–21.
2. Haffner SM, Lehto S, Rönnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in
nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-34.
3. Lee CD, Folsom AR, Pankow JS, et al. Cardiovascular events in diabetic and nondiabetic adults with or without history of
myocardial infarction. Circulation. 2004;109(7):855-60.
4. Services USDoHaH, Administration FaD, (CDER) CfDEaR. Guidance for industry diabetes mellitus-—evaluating cardiovascular risk
in new antidiabetic therapies to treat type 2 diabetes. Center for Drug Evaluation and Research Food and Drug Administration,
editor. 2008. https://www.fda.gov/downloads/Drugs/.../Guidances/ucm071627.pdf
5. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular
resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:1180-1193.
6. Neal B, Perkovic V, Mahaffer KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med
2017;377:644-657.
7. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;
375:311-322.
8. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with Type2 diabetes. N Engl J Med.
2016;375:1834-44.

Study Summary
Citation Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
N Engl J Med 2015;373:2117-28.
Objectives
Primary  To compare the effects of empagliflozin to placebo on composite outcome of CV death, nonfatal MI, or
Objectives nonfatal stroke in patients with T2DM and high risk for CV events
Secondary  To compare the effects of empagliflozin to placebo on the following outcomes in patients with T2DM and
objectives high risk for CV events:
o Composite of CV outcomes plus hospitalization from unstable angina
o Individual components of primary and secondary composite outcomes
o Changes in metabolic markers
o Safety
Methods
Study Design  Randomized, double-blind, placebo-controlled, multinational trial
 2-week open label, placebo run-in period

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  Background glucose lowering therapy to remain unchanged during first 12 weeks, then encouraged to adjust
accordingly
 Other cardiovascular agents were encouraged according to local guidelines
 Randomization from September 2010 – April 2013
Inclusion  At least 18 years old with a BMI <45 and eGFR ≥30
 Established cardiovascular disease defined as:
o History of MI, CAD, unstable angina, history of stroke, PAD
 Either no glucose-lowering agents for at least 12 weeks before randomization with HbA1C between 7%-9%
OR stable glucose-lowering agents for at least 12 weeks before randomization with HbA1C between 7%-
10%
Exclusion Uncontrolled hyperglycemia (fasting >240mg/dL), planned cardiac surgery within 3 months, acute coronary
syndrome, stroke, or transient ischemic attack within prior 2 months
Interventions  Placebo by mouth daily
/  Empagliflozin 10 mg by mouth daily
Comparator  Empagliflozin 25 mg by mouth daily
Primary  Composite outcome of death from CVD cause, nonfatal MI, or nonfatal stroke
Outcomes
Secondary  Primary composite outcome plus hospitalization for unstable angina, individual endpoints of the primary and
Outcomes secondary composite outcomes, metabolic markers (weight, waist circumference, BP, HR, LDL, HDL, uric
acid), safety
Statistics
Sample size  Hierarchical-testing
o Non-inferiority of primary outcome
o Non-inferiority of secondary outcomes
o Superiority for primary outcome
o Superiority for secondary outcome
 Non-inferiority for primary outcome - margin of 1.3 for HR with a one-sided alpha of 0.0249 OR Non-
inferiority of the primary outcome was determined if the upper boundary of the two-sided 95.02% CI was
less than 1.3
o 691 primary outcome events needed for 90% power on the assumption of a true hazard ratio of 1.0
Statistical  Modified intention to treat analysis
tests  Two-sided test with alpha ≤0.0498 was considered statistically significant
 Cox-proportional hazard model controlling for study group, age, BMI, sex, HbA1C, and geographic region
 Estimates of cumulative-incidence function were corrected for death as a competing risk and Kaplan-Meier
estimates was presented for death from any cause. Cumulative incidence plots were truncated at 48
months
Results
# of patients  Median duration of treatment: 2.6 years
 Median observation time: 3.1 years
 97% completed the study and 99% had known vital status
Total Placebo Empagliflozin 10 mg Empagliflozin 25 mg
mITT 7020 2333 2345 2342
Completed study 6809 2266 2264 2279
Discontinued drug 211 67 81 63
prematurely
Baseline  No significant differences in baseline characteristics
characteristics  Age 63 y/o, 70-72% male, 72% white
 BMI 31 kg/m2, 99% with CV risk factor (76% CAD, 47% MI, 10% cardiac failure), 95% on antihypertensives, BP
135/77 mmHg, 76-78% on statin therapy, LDL 85mg/dL, HDL86 mg/dL, Triglycerides 170 mg/dL
 HgA1C 8%, 74% on metformin
Primary Placebo Empagliflozin HR p-value
objectives (95% CI)
Noninferiority <0.001
mITT 282/2333 (12.1%) 490/4687 (10.5%) 0.86 (0.74-0.99)
Superiority 0.04
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 PP 278/2316 (12.0%) 487/4654 (10.5%) 0.86 (0.75-1.00) 0.05
 Both doses of empagliflozin were similar in effects, but were not statistically significant individually due to
the small number of events in each group 10 mg (HR 0.85; p=0.07) and 25 mg (HR 0.86; p=0.09)
Secondary Placebo Empagliflozin HR p-value
Objectives N=2333 N=4687 (95% CI)
Composite
599 Noninferiority <0.001
Outcome +unstable 333 (14.3%) 0.89 (0.78-1.01)
(12.8%) superiority 0.08
angina
194 269
Death from any cause 0.68 (0.57-0.82) <0.001
(8.3%) (5.7%)
172
Death from CV causes 137 (5.9%) 0.62 (0.49-0.77) <0.001
(3.7%)
Hospitalization from 95 126
0.65 (0.50-0.85) 0.002
heart failure (4.1%) (2.7%)
 Empagliflozin groups were statistically significant in reduction of HbA1C and average differences of between
empagliflozin and placebo were 0.24 to 0.60% depending on dose and duration
 Weight, waist circumference, systolic BP were slightly reduced in patients taking empagliflozin
Safety Data
Placebo Empagliflozin p-value
N=2333 N=4687
Any adverse event 2139 (91.7%) 4320 (90.2%) <0.001
Serious adverse event 592 (25.4%) 536 (22.9%) <0.05
Death from adverse event 119 (5.1%) 176 (3.8%) <0.01
Genital infection 42 (1.8%) 301 (6.4%) <0.001
Acute renal failure 155 (6.6%) 246 (5.2%) <0.01
Limitations  Limited number of events for each dose to observe potential dose response
 Relatively short-term data (median 3.1 yrs) for long-term morbidity and mortality
 Modest effect of empagliflozin in reducing HbA1C, weight, waist circumference, and systolic blood pressure
to explain the mechanisms for CV benefit
 Did not measure prognostic factors for the outcome such as cigarette smoking, lifestyle modification, or
exercise
Conclusion  In patients with T2DM and high risk for CVD, addition of empagliflozin to standard treatment resulted in 14%
relative risk reduction for the primary composite CV outcome. The reduction in the primary outcome is
primarily driven by 38% relative risk reduction in death from CV causes.
 There was 32% relative risk reduction in death from any cause and 35% relative reduction in the
hospitalization for heart failure.
 Empagliflozin was well tolerated with the increased rates of genital infection
 Future studies are needed to determine the mechanism behind the CV benefit and to determine the CV
benefit in patients without established CVD