Diabetes Management in the

Era of Cardiovascular Outcome Trial

 Contents
1. Management in T2DM : Beyond Glycemic Control
2. Empagliflozin : Additional cardioprotection on top of
standard of care
3. Established HbA1c efficacy, plus weight and blood
pressure reduction
4. Safety and tolerability
5. Summary and conclusion
6. Back-up

HbA1c, glycated haemoglobin 2

1. Management In T2DM : Beyond Glycemic Control
T2D is a global pandemic and a
major independent risk factor for complications

Associated complications of T2D2

Macrovascular Microvascular
• CV disease, e.g. stroke, • Diabetic nephropathy
myocardial infarction, • Diabetic retinopathy
peripheral artery disease • Diabetic neuropathy

Risk of developing CV disease is

2 to 4 times higher
2015 2040 in people with diabetes
Global diabetes incidence1 compared with people without3

CV, cardiovascular; T2D, type 2 diabetes

1. International Diabetes Federation. IDF Diabetes Atlas. 7th edn. 2015. www.idf.org/diabetesatlas; 2. World Health Organization. Diabetes
Programme – About diabetes. www.who.int/diabetes/action_online/basics/en/index3.html; 3. World Heart Federation. Diabetes. 2016. www.world-
heart-federation.org/cardiovascular-health/cardiovascular-disease-risk-factors/diabetes/ (all websites accessed May 2016) 4
 CV disease is an inevitable complication in T2D
Complex and multifactorial pathophysiological pathways in T2D are responsible for CV disease1

Stroke2

Coronary artery disease2 Heart failure3

Peripheral artery disease2 Acute myocardial infarction4

CV, cardiovascular; T2D, type 2 diabetes

1. Dokken BB. Diabetes Spectrum 2008;21:160;
2. World Health Organization. Types of cardiovascular disease. 2015. www.who.int/cardiovascular_diseases/en/cvd_atlas_01_types.pdf?ua=1;
3. American Heart Association. What is cardiovascular disease? 2014. www.heart.org/HEARTORG/Caregiver/Resources/WhatisCardiovascularDisease/What-is-Cardiovascular- 5
Disease_UCM_301852_Article.jsp#; 4. Thygesen K et al. Eur Heart J 2012;33:2551 (all websites accessed May 2016)
 CV disease is the number 1 cause of death
in patients with T2D1
Cause of death in patients with T2D2

Other
23%
CV disease

52% Cancer
14%

11%
Kidney disease
Mean follow-up was 9.4 years for men and 9.8 years for women; N=709
CV, cardiovascular; T2D, type 2 diabetes
1. International Diabetes Federation. IDF Diabetes Atlas. 7th edn. 2015. www.idf.org/diabetesatlas (accessed Mar 2016);
2. Morrish NJ et al. Diabetologia 2001;44 Suppl 2:S14
6
 Life expectancy is significantly decreased
in patients with T2D and established CV disease*

today End of life

No Diabetes

Diabetes -6 yrs

Diabetes +MI -12 yrs

In this case, CV disease is represented by MI or stroke. *Male, 60 years of age with history of MI or stroke
CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes 7
The Emerging Risk Factors Collaboration. JAMA 2015;314:52-60.
Despite receiving CV standard of care, patients with T2D and
established CV disease* are still at risk and
need additional cardioprotection

CV death
CV risk management1
Lipid management (e.g. statins)
Blood pressure control (e.g. ACEi/ARBs) ×1.7
Antithrombotic agents (e.g. ASA)

1
Patients with T2D
Glucose controlblood
Achieve glucose levels of ~7%†
(e.g. metformin, DPP-4i, SGLT2i, insulin)
are still at
almost double the risk of CV death
compared with the general population2

*Including coronary artery disease, peripheral artery disease, or a history of MI or stroke; †Reasonable goal for non-pregnant adults
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acid; CV, cardiovascular;
DPP-4i, dipeptidyl peptidase-4 inhibitor; MI, myocardial infarction; SGLT2i, sodium-glucose co-transporter-2 inhibitor; T2D, type 2 diabetes
1. American Diabetes Association. Diabetes Care 2016;39(Suppl 1):S1; 2. Centers for Disease Control and Prevention. National Diabetes Statistics Report.
2014. www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf (accessed May 2016)
8
 Can we do more to address CV risk?

?
CV, cardiovascular 9
2. Empagliflozin : Additional Cardioprotection
On Top of Standard of Care
 The CV effects of Empagliflozin were studied
in a dedicated CV outcomes trial published in the New England Journal of
Medicine

EMPA-REG OUTCOME® was a randomised, double-blind,

placebo-controlled CV outcomes trial1

7020 Patients 42 Countries 3.1 Years

Median observation time

Results were achieved on top of standard of care1

Patients’ CV risk factors, including glucose, were actively managed in placebo and
Empagliflozin treatment arms

95%* 81%* 89%* 98%*

Antihypertensive Lipid-lowering Anticoagulants1 Glucose-lowering
therapy1 therapy1 medications2

*Patients receiving therapy at baseline

CV, cardiovascular
1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Zinman B et al. Cardiovasc Diabetol 2014;13:102 11
Patients received Empagliflozin or placebo
on top of standard of care for CV and T2D management

Placebo + SOC (n=2333)

Randomised
Screening Empagliflozin 10 mg + SOC
and treated
(n=11,531) (n=2345)
(n=7020) Pooled*
Empagliflozin 25 mg + SOC
(n=2342)
• Glucose-lowering therapy was to remain
• Adults with T2D unchanged for the first 12 weeks
• BMI ≤45 kg/m2
• HbA1c ≥7% and ≤10%† • The trial was to continue until at least
• Established CV disease‡ 691 patients experienced an adjudicated primary
outcome event

*Data from both doses of Jardiance® were pooled for statistical analysis versus placebo; †Stable background therapy for ≥12 weeks before randomisation:
for insulin, dose was to remain unchanged by >10% from the dose received 12 weeks before randomisation); for drug-naïve: HbA1c ≥7% and ≤9%;
‡Including coronary artery disease, peripheral artery disease, or a history of MI or stroke

BMI, body mass index; CV, cardiovascular; HbA1c, glycated haemoglobin; MI, myocardial infarction; SOC, standard of care; T2D, type 2 diabetes
Zinman B et al. N Engl J Med 2015;373:2117 12
 In addition to T2D,
all patients had established CV disease

99%
Any CV
disease*

76% 47% 25% 23% 21% 10%

Coronary History Coronary History Peripheral Cardiac
artery of MI artery of artery failure‡
disease bypass stroke† disease
graft

Data are from patients treated with ≥1 dose of study drug

*Established CV disease including coronary artery disease, peripheral artery disease, or a history of MI or stroke; †Placebo, n=2332;
‡Based on narrow standardised MedDRA query ‘cardiac failure’

CV, cardiovascular; MedDRA, Medical Dictionary for Regulatory Activities; MI, myocardial infarction; T2D, type 2 diabetes
Zinman B et al. N Engl J Med 2015;373:2117 13
 EMPA-REG OUTCOME®
Key baseline characteristics
Placebo + Empagliflozin 10 mg + Empagliflozin 25 mg +
SOC (n=2333) SOC (n=2345) SOC (n=2342)
HbA1c, % (±SD) 8.08 (0.84) 8.07 (0.86) 8.06 (0.84)
Body mass index, kg/m2 (±SD) 30.7 (5.2) 30.6 (5.2) 30.6 (5.3)
SBP, mmHg (±SD) 135.8 (17.2) 134.9 (16.8) 135.6 (17.0)
DBP, mmHg (±SD) 76.8 (10.1) 76.6 (9.8) 76.6 (9.7)
LDL cholesterol, mg/l (±SD)* 84.9 (35.3) 86.3 (36.7) 85.5 (35.2)
HDL cholesterol, mg/l (±SD)† 44.0 (11.3) 44.7 (12.0) 44.5 (11.8)
eGFR, ml/min/1.73 m2 (±SD)‡ 73.8 (21.1) 74.3 (21.8) 74.0 (21.4)
≥90 ml/min/1.73 m2, n (%)‡ 488 (20.9) 519 (22.1) 531 (22.7)
60 to <90 ml/min/1.73 m2, n
1238 (53.1) 1221 (52.1) 1202 (51.3)
(%)‡
30 to <60 ml/min/1.73 m2, n
607 (26.0) 605 (25.8) 607 (25.9)
(%)‡
Data are from patients treated with ≥1 dose of study drug. *Placebo, n=2309; Jardiance® 10 mg, n=2317; Jardiance® 25 mg, n=2306;
†Placebo, n=2309; Jardiance® 10 mg, n=2318; Jardiance® 25 mg, n=2308; ‡Jardiance® 25 mg, n=2340

DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein;
LDL, low-density lipoprotein; SBP, systolic blood pressure; SD, standard deviation; SOC, standard of care 14
Zinman B et al. N Engl J Med 2015;373:2117
 Empagliflozin reduced CV death by 38%
on top of standard of care* in patients with T2D and established CV disease†

Placebo + SOC
HR 0.62 (n=2333)
(95% CI 0.49, 0.77)
p<0.001‡
Patients with event (%)

Empagliflozin + SOC
(n=4687)
38%
RRR in
CV death

Time (months)

Early and sustained reduction in CV death

Jardiance® in Indonesia is not indicated for CV risk reduction, and is not indicated for the treatment of HF or kidney disease
Pooled data from 10 mg and 25 mg doses of Jardiance®. The primary endpoint of the EMPA-REG OUTCOME® study was a composite of CV death, non-fatal
MI and non-fatal stroke (i.e. 3-point MACE). *SOC included CV medications (e.g. antihypertensive agents, lipid-lowering therapies and anticoagulants) and
glucose-lowering agents given at the discretion of the physician; †Including coronary artery disease, peripheral artery disease, or a history of MI or stroke;
‡Nominal p-value. CV, cardiovascular; HR, hazard ratio; MACE, major adverse CV events; MI, myocardial infarction; RRR, relative risk reduction; SOC,
15
standard of care; T2D, type 2 diabetes. Zinman B et al. N Engl J Med 2015;373:2117
 Empagliflozin reduced hospitalisation for heart failure by 35% on top of standard of
care*
in patients with T2D and established CV disease†

Placebo + SOC
HR 0.65 (n=2333)
(95% CI 0.50, 0.85)
p=0.002‡
Patients with event (%)

Empagliflozin + SOC
(n=4687) 35%
RRR in HHF

Time (months)

Early and sustained reduction in HHF

Jardiance® in Indonesia is not indicated for CV risk reduction, and is not indicated for the treatment of HF or kidney disease
Pooled data from 10 mg and 25 mg doses of Jardiance® used in the EMPA-REG OUTCOME® trial. *SOC included CV medications (e.g. antihypertensive
agents, lipid-lowering therapies and anticoagulants) and glucose-lowering agents given at the discretion of the physician; †Including coronary artery
disease, peripheral artery disease, or a history of MI or stroke; ‡Nominal p-value. CV, cardiovascular; HHF, hospitalisation for heart failure; HR, hazard ratio;
MI, myocardial infarction; RRR, relative risk reduction; SOC, standard of care; T2D, type 2 diabetes. Zinman B et al. N Engl J Med 2015;373:2117 16
 The mechanisms that explain the CV benefits
of Empagliflozin are likely to be multifactorial

Empagliflozin modulates several factors related to CV risk1

Haematocrit
Empagliflozin is
a reversible,
Intravascular volume
highly potent
SGLT2 inhibition in Systolic BP and selective
the kidney inhibitor of
SGLT22

Na+ & glucose excretion

Cardiac stress
Glomerular hypertension
Myocardial contractility
Diuresis
Renal oxygenation

Renal blood flow

BP, blood pressure; CV, cardiovascular;

SGLT2, sodium-glucose co-transporter-2
1. Sattar N et al. Diabetologia 2016;59:1333; 17
2. Jardiance® (empagliflozin) summary of product characteristics. 2016
The significance of the CV benefits seen in EMPA-REG
OUTCOME® has influenced clinical practice guidelines

Diabetes Canada pharmacologic management of T2D1

ESC guidelines for the diagnosis and treatment of acute and

chronic HF, and CV disease prevention in clinical practice2,3

AACE/ACE comprehensive T2D management algorithm 20174

American Diabetes Association 2017 standards of medical care in

diabetes5

AACE, American Academy of Clinical Endocrinologists; ACE, American College of Endocrinology;

CV, cardiovascular; ESC, European Society of Cardiology; HF, heart failure; T2D, type 2 diabetes.
1. Goldenberg R et al. Can J Diabetes 2016;40:193; 2. Ponikowski P et al. Eur Heart J 2016;37:2315;
3. Piepoli MF et al. Eur Heart J 2016;37:2129; 4. Garber AJ et al Endocr Pract 2016;22:84;
5. American Diabetes Association Diabetes Care 2017 40:S1
ADA released 2018 Standard of Medical Care in Diabetes

A Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Pharmacologic
ADA released 2018 Standard of Medical Care in Diabetes

In patients with T2DM and established ASCVD, antihyperglycemic therapy should begin with
lifestyle management and metformin and subsequently incorporate an agent proven to reduce
major adverse CV events and CV mortality (currently empagliflozin and liraglutide), after
considering drug-specific and patient factors (Table 8.1). A
A Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Pharmacologic 20
 ADA Standard of Medical Care in Diabetes
2017 vs 2018
2018 ADA Guideline
2017 ADA Guideline In patients with type 2 diabetes and established
atherosclerotic cardiovascular disease,
In patients with long-standing
antihyperglycemic therapy should begin with
suboptimally controlled type 2 diabetes lifestyle management and metformin and
and established atherosclerotic subsequently incorporate an agent proven to
cardiovascular disease, empagliflozin or reduce major adverse cardiovascular events
liraglutide should be considered as they and cardiovascular mortality (currently
have been shown to reduce empagliflozin and liraglutide), after considering
cardiovascular and all-cause mortality drug-specific and patient factors. A
when added to standard care. Ongoing
studies are investigating the
cardiovascular benefits of other agents in In patients with T2DM and established ASCVD,
these drug classes. B after lifestyle management and metformin, the
antihyperglycemic agent canagliflozin may be
considered to reduce major adverse CV events,
based on drug- specific and patient factors (Table
8.1). C
21
A Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85 Pharmacologic
ADA Evidence Grading System

22
3. Established Hba1c Efficacy, Plus Weight
and Blood Pressure Reduction
Empagliflozin provides established HbA1c efficacy
Effect seen across background glucose-lowering agents and in mild renal impairment

+ MET + Insulin Monotherapy

Monotherapy1 + MET2 + PIO3 + SU4 (78 weeks)5 in mild RI6
Adjusted mean (SE) difference vs

0.0
baseline in HbA1c (%)
in change from

-0.2
placebo

-0.5
-0.48 -0.46
-0.52
-0.57 -0.59
-0.7 -0.61 -0.62
-0.64 -0.64
-0.68
-0.74
-0.9 -0.85
Empagliflozin 10 mg Empagliflozin 25 mg
-1.1
Patients, n 224 224 217 213 165 168 225 216 169 155 98 97
BL HbA1c, % 7.87 7.86 7.94 7.86 8.07 8.06 8.07 8.10 8.30 8.30 8.02 7.96

Jardiance® in Indonesia is indicated as add-on therapy to metformin and SU.

All data are at Week 24, placebo-corrected and statistically significant unless otherwise marked. BL, baseline; HbA1c, glycated haemoglobin; MET, metformin; PIO, pioglitazone; RI, renal
impairment; SE, standard error; SU, sulphonylurea. 1. Roden M et al. Lancet Diabetes Endocrinol 2013;1:208; 2. Häring H-U et al. Diabetes Care 2014;37:1650; 3. Kovacs CS et al. Diabetes
Obes Metab 2014;16:147; 4. Häring H-U et al. Diabetes Care 2013;36:3396; 5. Rosenstock J et al. Diabetes 2013;(Suppl 1) (1102-P); 6. Barnett A et al. Lancet Diabetes Endocrinol 2014;2:369
Empagliflozin also reduces
body weight and systolic blood pressure*
Body weight Systolic blood pressure
Monotherapy1 Add-on to MET2 Monotherapy1 Add-on to MET2
0.0 0.0
Adjusted mean change from baseline

Adjusted mean change from baseline

-0.6
-1.3
-1.1
body weight, kg

SBP, mmHg
-2.5
-1.7 -2.6
-1.63
-1.93 -3.8 -3.4
-2.2 -2.01
-2.15 -4.1
-2.8 -5.0
-4.8
-3.3
-6.3

Patients, n 224 224 217 213 Patients, n 224 224 217 213

BL weight, 78.4 77.8 81.6 82.2 BL SBP, 133.0 129.9 129.6 130.0
kg mmHg

Empagliflozin 10 mg Empagliflozin 25 mg

Jardiance® in Indonesia is not indicated for weight loss or blood pressure reduction

All data are placebo corrected at Week 24. †p<0.0001; ‡p<0.001; §p=0.0231; ¶p=0.0028. BL, baseline; MET, metformin; SBP, systolic blood pressure
1. Roden M et al. Lancet Diabetes Endocrinol 2013;1:208; 2. Häring H-U et al. Diabetes Care 2014;37:1650
25
4. Safety and Tolerability
 Empagliflozin demonstrated safety and
tolerability in patients with T2D
Common AEs in phase III trials

• Overall incidence of AEs

10. 9.3
was similar to placebo
•
Adverse events (%)

7.6 7.6 Common AEs included

7.5
– hypoglycaemia,
– genital infections,
5. 4.1
3.7 3.4 3.2 – urinary tract infections,
– increased urination and
2.5
0.9 1.0 – pruritus
0. • In patients taking any kind of
Urinary tract infections Genital mycotic infections Increased urination SGLT2 inhibitors, rare cases
of diabetic ketoacidosis
Placebo Empagliflozin 10 mg Empagliflozin 25 mg have been reported

SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes

For a complete list of contraindications, warnings and precautions, please refer to Jardiance® Local Product Information, 2017. 27
Incidence of hypoglycaemia with Empagliflozin was similar to
placebo when used as monotherapy or added to metformin

30
27.1 Insulin and sulphonylureas are
Patients with confirmed hypoglycaemia* (%)

known to cause hypoglycaemia1

23 20.6 • Incidence of hypoglycaemic events*
19.5 was increased vs placebo
16.1 when Jardiance® was added
15 to a sulphonylurea or insulin
11.5 • When Jardiance® is used in
8.4 combination with a sulphonylurea
8 or with insulin,
a lower dose of the sulphonylurea
1.8
0.5
1.4
1
or insulin may be considered to
0 reduce the risk of hypoglycaemia
Add-on to MET Add-on2 to MET + SUAdd-on1to basal insulin

Placebo Empagliflozin 10 mg Empagliflozin 25 mg

Jardiance® in Indonesia is indicated as add-on therapy to metformin and SU.

*Confirmed events; plasma glucose ≤70 mg/dl and/or requiring assistance. MET, metformin; SU, sulphonylurea. 1. Häring H-U et al. Diabetes Care 2014;37:1650;
2. Jardiance® Local Product Information, 2017.; 3. Boehringer Ingelheim and Eli Lilly. Jardiance ® (empagliflozin) summary of product characteristics. 2016
 The safety profile of Empagliflozin was confirmed
in patients with T2D and established CV disease* in EMPA-REG OUTCOME®

Overall incidence of AEs, including diabetic ketoacidosis and bone fracture, was similar to placebo
Placebo + SOC Empagliflozin® 10 mg + Empagliflozin® 25 mg +
n (%) (n=2333) SOC SOC
(n=2345) (n=2342)
Confirmed hypoglycaemic AEs 650 (27.9) 656 (28.0) 647 (27.6)
Urinary tract infection 423 (18.1) 426 (18.2) 416 (17.8)
Complicated urinary tract 41 (1.8) 34 (1.4) 48 (2.0)
infection
Genital infection 42 (1.8) 153 (6.5) 148 (6.3)
Decreased renal function 155 (6.6) 121 (5.2) 125 (5.3)
(including acute kidney injury)
Volume depletion 115 (4.9) 115 (4.9) 124 (5.3)
Bone fractures 91 (3.9) 92 (3.9) 87 (3.7)
Venous thrombotic events 20 (0.9) 9 (0.4) 21 (0.9)
Diabetic ketoacidosis 1 (<0.1) 3 (0.1) 1 (<0.1)

Treated set (patients randomised and treated with ≥1 dose of study drug); *Including coronary artery disease, peripheral artery disease, or a history of
MI or stroke. CV, cardiovascular; MI, myocardial infarction; SOC, standard of care; T2D, type 2 diabetes. Zinman B et al. N Engl J Med 2015;373:2117 29
 Jardiance® (Empagliflozin) provides convenient
once-daily oral dosing for patients with T2D

Starting dose Increase to In patients who tolerate Jardiance®

10 mg and need additional
10 mg once daily1 25 mg once daily1* glycaemic control*

Jardiance® can be taken with or without food, at any time of the day1

Jardiance® is an SGLT2 inhibitor approved for use in patients with

eGFR ≥60 ml/min/1.73 m2. No dose adjustment needed1

Tablets are not actual size. *The maximum daily dose is 25 mg

eGFR, estimated glomerular filtration rate; SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes.
1. Jardiance® Local Product Information, 2017 30
5. Summary and Conclusion
Empagliflozin is the only T2DM agent approved as Grade A in International
Guideline (ADA), to provide additional cardioprotection* for patients with
T2D and established CV disease†

Patients with T2D and established Jardiance® also provides

CV disease are at high risk of CV established HbA1c efficacy3
death1 • With added benefits of
• High risk remains despite SOC reductions in body weight and
therapy blood pressure‡

Jardiance® reduced CV death by Jardiance® demonstrated safety

38%, on top of CV and glucose- and tolerability in a range of
lowering SOC2 patients with T2D3
• Jardiance® also reduced • With convenient, once-daily oral
hospitalisation for heart failure by dosing
35%‡

*Jardiance® is the only T2D agent approved to reduce the risk of CV death; †Including coronary artery disease, peripheral artery disease, or a history of MI or stroke;
‡Jardiance® is not indicated for heart failure, weight loss or blood pressure reduction. CV, cardiovascular; HbA1c, glycated haemoglobin; MI, myocardial infarction;

SOC, standard of care; T2D, type 2 diabetes. 1. Ryden L et al. Eur Heart J 2013;39:3035; 2. Zinman B et al. N Engl J Med 2015;373:2117; 3. Boehringer Ingelheim and
Eli Lilly. Jardiance® (empagliflozin) summary of product characteristics. 2016
 Now We Have..

“The Power to Protect”

7. Back-up

For internal use only. Strictly confidential. Do not copy or distribute.

EMPA-REG OUTCOME®
Key baseline characteristics
Placebo + Jardiance® 10 mg + Jardiance® 25 mg +
SOC (n=2333) SOC (n=2345) SOC (n=2342)
HbA1c, % (±SD) 8.08 (0.84) 8.07 (0.86) 8.06 (0.84)
Body mass index, kg/m2 (±SD) 30.7 (5.2) 30.6 (5.2) 30.6 (5.3)
SBP, mmHg (±SD) 135.8 (17.2) 134.9 (16.8) 135.6 (17.0)
DBP, mmHg (±SD) 76.8 (10.1) 76.6 (9.8) 76.6 (9.7)
LDL cholesterol, mmol/l* 2.20 2.23 2.21
HDL cholesterol, mmol/l† 1.14 1.16 1.15
eGFR, ml/min/1.73 m2 (±SD)‡ 73.8 (21.1) 74.3 (21.8) 74.0 (21.4)
≥90 ml/min/1.73 m2, n (%)‡ 488 (20.9) 519 (22.1) 531 (22.7)
60 to <90 ml/min/1.73 m2, n
1238 (53.1) 1221 (52.1) 1202 (51.3)
(%)‡
30 to <60 ml/min/1.73 m2, n
607 (26.0) 605 (25.8) 607 (25.9)
(%)‡
Data are from patients treated with ≥1 dose of study drug. *Placebo, n=2309; Jardiance® 10 mg, n=2317; Jardiance® 25 mg, n=2306;
†Placebo, n=2309; Jardiance® 10 mg, n=2318; Jardiance® 25 mg, n=2308; ‡Jardiance® 25 mg, n=2340

DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein;
LDL, low-density lipoprotein; SBP, systolic blood pressure; SD, standard deviation; SOC, standard of care 35
Zinman B et al. N Engl J Med 2015;373:2117
 EMPA-REG OUTCOME®
baseline CV medication in detail (1)
Placebo + SOC Jardiance® 10 mg + Jardiance® 25 mg +
(n=2333) SOC (n=2345) SOC (n=2342)
Antihypertensive therapy, n (%) 2221(95.2) 2227(95.0) 2219(94.7)
ACE inhibitors/ARBs 1868(80.1) 1896(80.9) 1902(81.2)
Beta-blockers 1498(64.2) 1530(65.2) 1526(65.2)
Diuretics 988(42.3) 1036(44.2) 1011(43.2)
Calcium channel blockers 788(33.8) 781(33.3) 748(31.9)
Mineralocorticoid
136(5.8) 157(6.7) 148(6.3)
receptor antagonists
Other 210(9.0) 209(8.9) 201(8.6)

Data are from patients treated with ≥1 dose of study drug

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CV, cardiovascular; SOC, standard of care
Zinman B et al. N Engl J Med 2015;373:2117 36
 EMPA-REG OUTCOME®
baseline CV medication in detail (2)
Placebo + SOC Jardiance® 10 mg + Jardiance® 25 mg +
(n=2333) SOC (n=2345) SOC (n=2342)
Lipid-lowering drugs, n (%) 1864(79.9) 1926(82.1) 1894(80.9)
Statins 1773(76.0) 1827(77.9) 1803(77.0)
Fibrates 199(8.5) 214(9.1) 217(9.3)
Ezetimibe 81(3.5) 95(4.1) 94(4.0)
Other 210(9.0) 228(9.7) 228(9.7)
Anticoagulants and antiplatelets, n (%) 2090(89.6) 2098(89.5) 2064(88.1)
Acetylsalicylic acid 1927(82.6) 1939(82.7) 1937(82.7)
Clopidogrel 249(10.7) 253(10.8) 241(10.3)
Vitamin K antagonists 156(6.7) 141(6.0) 125(5.3)

Data are from patients treated with ≥1 dose of study drug

CV, cardiovascular; SOC, standard of care
Zinman B et al. N Engl J Med 2015;373:2117 37
 EMPA-REG OUTCOME®
baseline characteristics T2D
Placebo + SOC Jardiance® 10 mg + SOC Jardiance® 25 mg + SOC
(n=2333) (n=2345) (n=2342)
Age, years (±SD) 63.2(8.8) 63.0(8.6) 63.2(8.6)
Male, n (%) 1680(72.0) 1653(70.5) 1683(71.9)
HbA1c, % (±SD) 8.08(0.84) 8.07(0.86) 8.06(0.84)
Time since diagnosis of type 2 diabetes, n (%)
≤5 years 423(18.1) 406(17.3) 434(18.5)
>5–10 years 571(24.5) 585(24.9) 590(25.2)
>10 years 1339(57.4) 1354(57.7) 1318(56.3)
Glucose-lowering medication, n (%)*
Metformin 1734(74.3) 1729(73.7) 1730(73.9)
Sulphonylureas 992(42.5) 985(42.0) 1029(43.9)
DPP-4 inhibitors 267(11.4) 282(12.0) 247(10.5)
Thiazolidinediones 101(4.3) 96(4.1) 102(4.4)
Insulin 1135(48.6) 1132(48.3) 1120(47.8)
Median daily dose, IU† 52.0 52.5 54.0

Data are from patients treated with ≥1 dose of study drug. *Medication taken alone or in combination; †Placebo, n=1135; Jardiance® 10 mg, n=1132; Jardiance® 25 mg,
n=1120. DPP-4, dipeptidyl peptidase-4; HbA1c, glycated haemoglobin; IU, international unit; SD, standard deviation; SOC, standard of care; T2D, type 2 diabetes. Zinman 38
B et al. N Engl J Med 2015;373:2117
Heart failure is a serious condition
that significantly impairs quality of life
• Heart failure is a condition in
which the heart is unable to pump Typical symptoms3–5
sufficiently to maintain the Breathlessness
Increased urination at night
metabolic needs of tissues in the Reduced exercise tolerance
body1,2 Tiredness
• Myocardial infarction and
hypertension are the most
common causes2
Typical signs3
Elevated pressure of jugular vein
Displaced heart beat
Third heart sound
Crackling lung sounds
Ankle swelling

1. Coronel R et al. Cardiovasc Res 2001;50:419; 2. Yancy CW et al. Circulation 2013;128:e240; 3. McMurray JJV et al. Eur Heart J
2012;33:1787; 4. Kemp CD & Conte JV. Cardiovasc Pathol 2012;21:365; 5. Redekar NS et al. J Card Fail 2012;18:569
39
 Diabetes is associated with a worse prognosis in
patients with heart failure
CV death or HHF in patients with or without diabetes

60 HFrEF: unadjusted HR 1.60 Diabetes No diabetes

(95% CI 1.44, 1.77); p<0.0001
HFrEF
HFpEF: unadjusted HR 2.0
(95% CI 1.70, 2.36); p<0.0001
Cumulative incidence (%)

40
HFpEF
HFrEF

20 HFpEF

0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Follow-up (years)

HRs refer to the risk of CV death or HHF in patients with diabetes versus non-diabetes. CV, cardiovascular; HFpEF, heart failure with preserved ejection fraction; HFrEF,
heart failure with reduced ejection fraction; HHF, hospitalisation for heart failure; HR, hazard ratio
MacDonald MR et al. Eur Heart J 2008;29:1377 40
Reduction in CV death was consistent
in patients with T2D, irrespective of renal function

CV death HR (95% CI)

Subgroup analysis of patients
All patients
stratified by renal function at
eGFR, ml/min/1.73 m2
baseline showed consistent
≥90
hazard ratios (i.e. risk
60 to <90
reduction) for CV death,
<60
even in patients with
0.25
worsening renal function
Favours Jardiance® Favours placebo

Pooled data from 10 mg and 25 mg doses of Jardiance®

CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; T2D, type 2 diabetes
Zinman B et al. N Engl J Med 2015;373:2117 41
 Jardiance® reduced all-cause mortality by 32% on top of
standard of care* in patients with established CV disease

HR 0.68
Placebo + SOC
(95% CI 0.57, 0.82)
(n=2333)

32%
p<0.0001†
Patients with event (%)

RRR in all-
Jardiance® + SOC (n=4687) cause
mortality

Time (months)

Jardiance® is not indicated for reducing the risk of all-cause mortality

Pooled data from 10 mg and 25 mg doses of Jardiance®. *SOC included CV medications (e.g. antihypertensive agents, lipid-lowering therapies and
anticoagulants) and glucose-lowering agents given at the discretion of the physician; †Nominal p-value. CV, cardiovascular; HR, hazard ratio; 42
RRR, relative risk reduction; SOC, standard of care; Zinman B et al. N Engl J Med 2015;373:2117
 Treating 1000 patients with T2D and established CV disease with
Jardiance® on top of standard of care for 3 years could…

…prevent
…prevent
22 CV deaths 14 hospitalisations for
heart failure

Placebo Jardiance®

CV, cardiovascular; T2D, type 2 diabetes 43

Zinman B. EASD 2015; Oral presentation
Renal function was maintained with Jardiance® in
patients with T2D and established CV disease
Fewer patients experienced acute renal failure (including acute kidney injury) compared with
placebo

Placebo + SOC
78
Jardiance® 10 mg + SOC
76
Adjusted mean (SE) eGFR

Jardiance® 25 mg + SOC
(ml/min/1.73m2)

74

72

70

68

66
Week
04 12 28 52 66 80 94 108 122 136 150 164 178 192

CV, cardiovascular; eGFR, estimated glomerular filtration rate; SE, standard error; SOC, standard of care; T2D, type 2 diabetes
Wanner C et al. N Engl J Med 2016;doi:10.1056/NEJMoa1515920 44