Addressing CV Risk in the

management of diabetes

Dr Rajesh Jain

1
 The size of
the
problem

CV Risk
in
Additional
Diabetes
risk factors Patho-
are
common in physiology
T2D

2
CVD is a significant global burden

7.4
million
due to
CHD

31% due
to CVD 6.7
million
due to
stroke

Total global deaths

in 2012 ~56 million1

The size of
the
3 problem
1. WHO. CVD Fact sheet N°317, Jan 2015. http://www.who.int/mediacentre/factsheets/fs317/en/#.
T2D is increasingly prevalent and CVD is the
leading cause of death in this population
• Globally, 387 million people are • T2D approximately doubles the
living with diabetes1 risk of death2

Relative risk for

1.85 all-cause mortality

Relative risk for

1.76 CV mortality

1 1.5 2.0

• Diabetes caused 4.9 million

deaths in 20141
• CVD is the principal cause of
• Rising to 592 million by 20351 death in T2D2,3
Represents 2 million people.
Diabetes is mostly (85–95%) T2D.1
1. IDF Diabetes Atlas, 2014. 6th Edition. http://www.idf.org/diabetesatlas.
2. Nwaneri et al. Br J Diabetes Vasc Dis 2013;13:192–207. 3. Morrish et al. Diabetologia 2001;44(suppl 2):S14–21.

4
 Diabetes is associated with significant loss of
life years
Men Women
7 7
Non-vascular deaths
6 Vascular deaths 6

5 5
Years of life lost

4 4

3 3

2 2

1 1

0 0
0 40 50 60 70 80 90 0 40 50 60 70 80 90
Age (year) Age (year)
On average, a 50-year old with diabetes but no history of vascular disease is
~6 years younger at time of death than a counterpart without diabetes
Seshasai et al. N Engl J Med 2011;364:829-41.

5
 Glucose-lowering studies confirmed benefit on microvascular
complications but mixed results on macrovascular outcomes

Mean duration of
Study Baseline HbA1C diabetes at
Control vs intensive baseline (years) Microvascular CVD Mortality

UKPDS 9% 7.9% vs 7% Newly diagnosed ↓ ↓ ↔ ↓ ↔ ↓

ACCORD 8.3% 7.5% vs 6.4% 10.0 ↓ ↔ ↑
ADVANCE 7.5 % 7.3% vs 6.5% 8.0 ↓ ↔ ↔
VADT 9.4 % 8.4% vs 6.9% 11.5 ↓ ? ↔ ↓ ↔ ↔
Long-term follow-up: 20 years
Long-term follow-up: 10 years2

1. Table adapted from Bergenstal et al. Am J Med 2010;123:374.e9–e18. Glycaemic

6 2. Hayward et al. N Engl J Med 2015;372:2197-206.
control
UKPDS 34 provides some evidence for beneficial CV effects
of metformin in overweight patients
Risk of MI is 39% lower with metformin vs Significant reduction in MI maintained
conventional therapy in obese patients1,2 over 10 years’ follow-up3
Proportion of patients with events (%)

Myocardial infarction Overall values at study end in 1997

30 Conventional (n = 411; events = 73)
Annual values during 10-year post-trial monitoring period
Intensive (n = 951; events = 139)
Metformin (n = 342; events = 39) 1.4 RR 0.611 RR 0.67
p = 0.01 p = 0.005

HR (95% CI)
20 1.2
Metformin vs 1.0
conventional
p = 0.01 0.8
10
0.6
0.4
0.0 1997 1999 2001 2003 2005 2007
0 3 6 9 12 15 No. of events:
Time from randomisation (years) Conventional 73 83 92 106 118 126
therapy
Metformin 39 45 55 64 68 81

Met-
for-
7 1. UKPDS 34. Lancet 1998;352:854–65. 2. http://www.medicines.org.uk/emc/medicine/23244/SPC.
3. Holman et al. N Engl J Med 2008;359:1577–89. min
Meta-analysis of SU CV safety trials (≥ 6 months) found no
consistent association with MACE risk
MH-OR (95% CI)
First author (year) Total # patients* Total # events*
Birkeland 1996 36 1
Chou 2008 452 3
Perriello 2006 283 9
Gerstein 2010 672 55
UKPDS 33 1998 3041 610
Hanefeld 2007 587 4
Seino 2010 400 4
Charbonnel 2005 630 14
Matthews 2005 1250 15
Rubin 2008 1805 46
Home 2009 2222 312
Arechavaleta 2011 1035 4
va der Laar 2004 96 2
Mazzone 2006 458 4
Riddle 1998 145 2
Giles 2010 300 26
Tolman 2009 2097 61
Kahn 2006 4351 72
Goke 2010 858 13
Garber 2009 495 13
Nissen 2008 543 24
Ristic 2007 262 5
Ferrannini 2009 2789 34
Bakris 2006 374 11
Gallwitz 2012 1551 38
Jain 2006 502 11
Johnston 1998 272 4
Nauck 2011 801 3
Seck 2010 1172 4
Overall 29,783 1495

0.01 0.1 1 10 100

Favours SUs Favours comparators

Overall MACE risk estimate for SU vs comparators was not

increased: MH-OR 1.08 (95% CI: 0.86–1.36); p = 0.52
*SU + comparator groups combined.
Monami et al. Diabetes Obes Metab 2013;15:938–53.

8 FOR INTERNAL USE ONLY, SU

DO NOT DETAIL OR DISTRIBUTE
CV safety of SUs

• The UGDP study raised safety concerns with tolbutamide (excess of

cardiac deaths vs placebo)1
• UKPDS 33 demonstrated no deleterious effect of SUs on CV safety
compared with insulin or conventional management2
• In a meta-analysis of 115 trials, overall MACE risk estimate for SUs vs
comparators was not increased (OR 1.08)3

‘CV safety of SUs cannot be considered established

unless evaluated in long-term CVOTs’4

9 1. Meinert et al. Diabetes 1970;19(suppl):789–830. 2. UGDP. Diabetes 1970;19(suppl 2):747–830. 3. UKPDS Group. SU
Lancet 1998;352:837–53. 4. Monami et al. Diabetes Obes Metab 2013;15:938–53.
Certain glucose-lowering therapies have been associated with
CV adverse events

UGDP study: tolbutamide discontinued due to

1961
increased CV mortality vs other treatment groups1

Muraglitazar found to potentially increase CV • Sponsor withdrew

2005 application1
risk during FDA assessment2

2007
Rosiglitazone associated with increased risk • Withdrawn in the
for MI and CV-related death3 EU/India in 2010
ACCORD study: intensive glucose lowering was • Use restricted in the
2008 US and the restriction
associated with increased all-cause mortality4
HR 1.22 (95% CI: 1.01‒1.46); p = 0.04 were removed in 2014

2008 New FDA requirements5

2012 New EMA requirements6
New diabetes drugs should demonstrate CV safety
with meta-analysis and a CVOT

1. Nissen. Ann Intern Med 2012;157:671–2. 2. Nissen et al. JAMA 2005;294:2581–6. 3. Nissen et al. N Engl J Med FDA
10
2007;356:2457–71. 4. ACCORD Study Group. N Engl J Med 2008;358:2545–59. 5. FDA Guidance for Industry. 6. EMA
Guidelines. 7. FDA Safety Information.
mandate
In 2007, separate meta-analyses suggested differing CV
effects of drugs within the TZD class
Rosiglitazone meta-analysis1 Pioglitazone meta-analysis2

MI
MI
HR 0.81 (95% CI: 0.64‒1.02)
OR 1.43 (95% CI: 1.03‒1.98)
p = 0.08
p = 0.03

Death
CV death HR 0.92 (95% CI: 0.76‒1.11)
OR 1.64 (95% CI: 0.98‒2.74) p = 0.38
p = 0.06

0.5 1.0 2.0 0.5 1.0 2.0

Favours Favours control Favours Favours control

rosiglitazone pioglitazone

No clinical trial directly compares the CV effects of pioglitazone and rosiglitazone

11 1. Nissen & Wolski. N Engl J Med 2007;356:2457–71. 2. Lincoff et al. JAMA 2007;298:1180–8. TZD
CV safety of TZDs

• TZDs cause or exacerbate congestive heart failure in some patients1

• CV meta-analyses in 2007 suggested differing effects on CV outcomes
• Pioglitazone was associated with a significant 16% reduction in
3P-MACE (as a secondary endpoint) vs placebo in PROactive2
• Rosiglitazone open-label RECORD data showed no increase in
CV death1
• FDA reduced the safety restrictions on rosiglitazone imposed following
2007 meta-analysis3 but controversy over CV safety remains

‘Within the PPAR family, there is no “class effect” and each agent
must be considered unique. The FDA has mandated that each agent
within this class be evaluated individually in a variety of ways
including clinical outcome studies’4

12 1. AVANDIA US Prescribing information. 2. Dormandy et al. Lancet 2005;366:1279–89. 3. FDA Safety Information. TZD
4. Rosenson et al. Am Heart J. 2012;164:672–80.
 Regulatory requirements for drug-specific CV outcome data
in T2DM
FDA 2008 Guidance for Industry1 EMA 2012 Guideline2

‘To establish the safety of a new anti-

diabetes drug to treat T2D, sponsors
should demonstrate that the therapy will
not result in an unacceptable increase in
CV risk.’
• Important CV events should be
analysed
• High-risk population to be included
• Long-term data required (≥ 2 years)
• Prospective adjudication of CV events
by an independent committee
• Phase II and III trials designed and
conducted to permit meta-analysis to
be performed at completion
‘A fully powered CV safety assessment,
e.g., based on a dedicated CV outcome
study, should be submitted before
marketing authorisation whenever a
safety concern is intrinsic in the
molecule/MOA or has emerged from pre-
clinical/clinical registration studies.’
Two approaches are recommended:
• Meta-analysis of safety events
• Specific long-term controlled outcome
study with at least 18–24 months’
follow-up

13
1. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.
2. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf.
 FDA requirements for CV outcome data:
Meta-analysis* limits and outcome trial requirements
Increased
risk

1.3 – 1.8
Relative CV risk

Upper boundary of 95% confidence limit of risk ratio point estimate

Postmarketing CV trial(s)
Postmarketing CV trial(s)
needed to show Inadequate data to support
generally not necessary if
definitively < 1.3 if the risk approval
the risk ratio is reassuring*
ratio is reassuring*
Safe
*Studies included in the meta-analysis must be appropriately designed and specifically include patients at higher risk of CV
events to obtain sufficient endpoints to allow a meaningful estimate of risk. 1. FDA Guidance for Industry.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.
 Evolution of T2D agents
Only the newer agents have dedicated CVOTs
The CV safety of older drugs are ascertained through other studies
DPP4 SGLT2
inhibitors inhibitors

 Older T2D agents Newer T2D agents 

1950 1960 1970 1980 1990 2000 2010 2012 2013

GLP1 receptor
agonists
Lente class Recombinant Glimepiride: Insulin
of insulins human insulin 3rd generation SU degludec
produced produced

SUs first used 2nd generation

SUs available Insulin glargine
available2
Metformin
Metformin Three new classes introduced:
introduced
introduced -glucosidase inhibitors, meglitinides
and TZDs
in the UK

15 Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. 2. Lantus ® SPC.

 Overview of CVOTs of glucose-lowering drugs

SAVOR-TIMI 531 OMNEON13 CAROLINA®11

(n = 16,492) (n = 4000) (n = 6000)
1,222 3P-MACE 4P-MACE ≥ 631 4P-MACE
EXAMINE2 TECOS4 CARMELINA12
(n = 5380) (n = 14,724) (n = 8300)
621 3P-MACE ≥ 1300 4P-MACE 4P-MACE + renal

2013 2014 2015 2016 2017 2018 2019 2021

ELIXA3 EXSCEL14 REWIND16

(n = 6068) SUSTAIN-67
(n = 3297) (n = 14,000) (n = 9622)
≥ 844 4P-MACE ≥ 1591 3P-MACE ≥ 1067 3P-MACE
3P-MACE
ITCA CVOT9 DECLARE-TIMI 5815
(n = 4000) (n = 17,150)
LEADER6 4P-MACE ≥ 1390 3P-MACE
DPP4 inhibitor
CVOTs (n = 9340) CANVAS10 CREDENCE17
≥ 611 3P-MACE (n = 4365) (n = 3700)
SGLT2 inhibitor ≥ 420 3P-MACE Renal + 5P-MACE
CVOTs EMPA-REG
OUTCOME™5 Ertugliflozin CVOT18
(n = 7034) CANVAS-R8
GLP1 CVOTs (n = 5700) (n = 3900)
≥ 691 3P-MACE 3P-MACE
Albuminuria

CVOT
Timings represent estimated completion dates as per ClinicalTrials.gov. interpre-
16 Adapted from Johansen. World J Diabetes 2015; in press (references 1–18 expanded in slide notes) tation
 The size of
the
problem

CV Risk
in
Additional
Diabetes
risk factors Patho-
are
common in physiology
T2D

17
Modifiable CV risk factors are common in patients
with T2D1,2

Almost a third of diabetes patients were current smokers2

1. Svensson et al. Diab Vasc Dis Res 2013;10:520–9. 2. Das et al. Am Heart J 2006;151:1087–93.

18
CV death is increased in patients with diabetes and
multiple risk factors

Diabetes
140
No diabetes
Age-adjusted CVD death
risk/10,000 person-years

120
100
80
60
40
20
0
0 1 2 3
Number of risk factors

Risk factors were serum cholesterol ≥200 mg/dL, current smoker, SBP ≥120 mmHg
Stamler et al. Diabetes Care 1993;16:434.

19
 Control of
LDL-
cholesterol

Antihypertensive Antiplatelet
therapy therapy
↓CV
risk
Reducing CV risk in T2D requires a multifactorial approach

Weight loss
Glycaemic
and lifestyle
control
intervention*

*Includes smoking cessation.

Rydén et al. Eur Heart J 2013;34:3035–87.

20
Steno-2: Intensive multifactorial control of CV risk factors
reduces CV risk in patients with T2D and microalbuminuria

60
Conventional
Primary composite

50 Unadjusted HR 0.47 (85 events)

(95% CI: 0.24‒0.73); p = 0.008
endpoint (%)

40
30 Intensive
(33 events)
20
10
0
0 12 24 36 48 60 72 84 96
Months of follow-up

Composite endpoint: CV death, non-fatal MI, non-fatal stroke revascularisation and amputation.
Gaede et al. N Engl J Med 2003;348:383–93.

21
 Management
of Diabetes

Achieving Managing Achieving

Safety
Short term goal Co-morbidities Long term goals

Minimize Sustained
FPG Hypertension
Hypoglycemia glycemic control

Minimize
PPG Dyslipidemia Reduce CV risk
Weight gain

Reduce
Minimize other
HbA1c Obesity progression of
side effects
nephropathy

22
GLP1 has various potential effects on the CV system:
Data derived from non-clinical and mechanistic proof-of-concept studies

Pancreas Brain
↑ Insulin secretion
↓ Glucagon secretion
Heart
↑ Insulin biosynthesis ↓ Appetite
↑ β-cell proliferation ↑ Neuroprotection
↓ β -cell apoptosis ↑ Endothelial function
↑ Nitric oxide production

Incretin ↑ ↓ Myocardial contractility (data conflict)

↑ Systolic function in myocardial infarction
hormone1,2
↑ Systolic function in cardiomyopathy

Liver Muscle and ↓ Infarct size

adipose tissue ↑ Ischaemic pre-conditioning
↑ Post-ischaemic recovery
↓ Insulin sensitivity
↓ Glucose output ↑ Myocardial glucose uptake
(direct or indirect?)

Clinical trial data shows that GLP1 analogues are associated with small increases in heart
rate and modest reductions in body weight and blood pressure3

GLP1
23 1.3. Jax. Clin Res Cardiol 2009;98:75–9. 2. Grieve. Br J Pharmacol 2009;157:1340–51 (modified).
Robinson et al. BMJ Open 2013;3:pii e001986.
agonists
Selected mechanistic trials indicate CV effects
of the DPP4 inhibitor class

Myocardial Endothelial
infarct size1,2 function3

Inflammation and
Triglycerides8 oxidative stress4

Left
Atherosclerotic
ventricular
plaque volume5
function6,7

1. Ye et al. Am J Physiol Heart Circ Physiol 2010;298:H1454–65. 2. Hocher et al. Int J Cardiol 2013;167:87–93.
3. van Poppel et al. Diabetes Care 2011;34:2072–77. 4. Kröller-Schön et al. Cardiovasc Res 2012;96:140–9. DPP4
25 5. Ta et al. J Cardiovasc Pharmacol 2011;58:157–66. 6. Sauvé et al. Diabetes 2010;59:1063–73.
inhibitors

7. Read et al. Circ Cardiovasc Imaging 2010;3:195–201. 8. Matikainen et al. Diabetologia 2006;49:2049–57.
 3 possible results of CV outcome trials

CV outcome trials primary endpoint All patients receive standard-of-care

3P-MACE: CV death, nonfatal MI, nonfatal stroke treatment in addition to the study drug
4P-MACE: CV death, nonfatal MI, nonfatal
or placebo
stroke, unstable angina requiring hospitalisation

Empagliflozin

CV PROTECTION
Superiority to placebo

+ CV SAFETY
Non-inferiority to placebo
Sitagliptin,
Saxagliptin

INCREASES CV RISK
- Inferiority to placebo Muraglitazar

MACE: major adverse cardiac events

 The size of
the
problem

CV Risk
in
Additional
Diabetes
risk factors Patho-
are
common in physiology
T2D

28
 Visceral adiposity is related to inflammation, insulin
resistance, dyslipidaemia and atherosclerosis
Interactions are complex, inter-related and not necessarily causal

Dyslipidaemia

 Adiponectin Endothelial
T2D dysfunction

OBESITY Adipocytokines Hypertension  Atherosclerosis

Insulin
resistance
 inflammatory Age
cytokines*

 Oxidative
stress

*including: TNFα, IL-6, resistin, PAI-1, angiotensinogen

Lau et al. Am J Physiol Heart Circ Physiol 2005;288:H2031‒41.

29
 Impact of current anti-diabetic agents on diabetes
management
Anti-diabetic Efficacy Minimize Effect on Impact on Reduce CV Reduce
drug hypoglycemia weight co- risk progression of
morbidities nephropathy
Metformin Potential effect
in subgroup of
UKPDS
Sulfonylureas

TZDs

AGIs

DPP4
inhibitors
GLP-1 RA

SGLT2 EMPA REG

inhibitors OUTCOME

Insulin

Neutral Adverse Beneficial

30
 Recent trials of newer glucose-lowering agents have been
neutral on the primary CV outcome until EMPA REG
OUTCOME
HR: 1.0 SAVOR-TIMI 53 HR: 0.98 TECOS
(95% CI: 0.89, 1.12) (saxagliptin) (95% CI: 0.88, 1.09) (sitagliptin)

HR: 0.96 EXAMINE

(95% CI: UL ≤1.16) (alogliptin)

2013 2014 2015

HR: 1.02 ELIXA

(95% CI: 0.89, 1.17) (lixisenatide)
DPP-4 inhibitors*

Lixisenatide EMPA-REG OUTCOME®

(empagliflozin)
Empagliflozin

31
 Patients with T2D at
11,531 >97 % >99 % high CV risk
pts screened completed vital status
trial available
7020 pts
randomized

Placebo
On top of
Empagliflozin 10 mg standard of
Randomisation care*
Empagliflozin 25 mg
Target: ≥691 CV events
* Good quality standard of care including background glucose lowering agents and cardiovascular
32 therapy common to both arms. CV, cardiovascular.
Participating countries
590 sites from 42 countries

Indian
patients*

Asia
North America, Australia,
New Zealand
Latin America
Europe
Africa * 280 Indian patients enrolled, 163 randomized

33
 14% RRR
Primary outcome: In CV Death +
MI + Stroke
3-point MACE

HR 0.86
(95.02% CI 0.74, 0.99)
p=0.0382*
CV death 38% RRR
In CV Death

HR 0.62
(95% CI 0.49, 0.77)
p<0.0001

35
 CV death, MI and stroke

Patients with event/analysed

Empagliflozin Placebo HR (95% CI) p-value

3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382

CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001

Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189

Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638

Reduction in 3P-MACE driven by CV death with a 0.25 0.50 1.00 2.00

non-significant impact on non fatal MI or stroke Favours empagliflozin Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event;
36 HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction
*95.02% CI
Hospitalisation for heart failure 35% RRR
In HHF

HR 0.65
(95% CI 0.50, 0.85)
p=0.0017

37
All-cause mortality 32% RRR
In Death due
to any cause

HR 0.68
(95% CI 0.57, 0.82)
p<0.0001

38
 Heart failure outcomes and all-cause European Heart
Journal Jan 2016
hospitalization
Outcome Placebo (N=2333) Empagliflozin (N=4687)
HR
n (%) Rate/1000 n (%) Rate/1000 p-value
(95% CI)
pt-years pt-years

Heart failure hospitalisation or 198 (8.5) 30.1 265 (5.7) 19.7 0.66 (0.55–0.79) <0.001
CV death
Hospitalisation for or death 104 (4.5) 15.8 129 (2.8) 9.6 0.61 (0.47–0.79) <0.001
from heart failure
Hospitalisation for heart 95 (4.1) 14.5 126 (2.7) 9.4 0.65 (0.50–0.85) 0.002
failure
Investigator-reported heart 143 (6.1) 22.0 204 (4.4) 15.3 0.70 (0.56–0.87) 0.001
failure*
Investigator-reported serious 136 (5.8) 20.9 192 (4.1) 14.4 0.69 (0.55–0.86) 0.001
heart failure*†
All-cause hospitalisation 925 (39.6) 183.3 1725 (36.8) 161.9 0.89 (0.82–0.96) 0.003

Patients treated with at least one dose of study drug.

CI, confidence interval; HR, hazard ratio; MedDRA, Medical Dictionary for Regulatory Activities.
39 *Based on narrow standardised MedDRA query “cardiac failure”.
†Adverse events reported as serious adverse events by investigator. David Fitchett, et al. Eur Heart J 2016 [Epub ahead of print].
Outcomes consistent in patients with vs European Heart
Journal Jan 2016
without heart failure at baseline

40 Cox regression analysis. HF, heart failure; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.
David Fitchett, et al. Eur Heart J 2016 [Epub ahead of print].
SGLT2 inhibitors modulate a range of factors
related to CV risk
Based on clinical and mechanistic studies

Novel
Pathways (?)

 Blood pressure
 Arterial
stiffness  Albuminuria

 SNS
 SNS
activity (?)  Uric Acid
activity (?)  Glucose
 Insulin

 Weight  LDL-C
 Visceral  HDL-C
adiposity  Triglycerides
 Oxidative
stress

Inzucchi et al. Diab Vasc Dis Res 2015;12:90‒100.

41
Number needed to treat (NNT) to prevent one death across
major trials in patients with high CV risk
(lower the NNT, the better)

Simvastatin1 Ramipril2 Empagliflozin

for 5.4 years for 5 years for 3 years

High CV risk High CV risk T2DM with high CV risk

5% diabetes, 26% hypertension 38% diabetes, 46% hypertension 92% hypertension

Pre-ACEi/ARB era >80% ACEi/ARB

Pre-statin era <29% statin >75% statin

1994 2000 2015

• CV, cardiovascular; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
42 1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4S.htm;
2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-HOPE.htm
Number needed to treat (NNT) to prevent one death across
major trials in patients with high CV risk
(lower the NNT, the better)

Simvastatin1 Ramipril2 Empagliflozin

for 5.4 years for 5 years for 5 years

High CV risk High CV risk T2DM with high CV risk

5% diabetes, 26% hypertension 38% diabetes, 46% hypertension 92% hypertension

Pre-ACEi/ARB era >80% ACEi/ARB

Pre-statin era <29% statin >75% statin

1994 2000 2015

• CV, cardiovascular; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker.
43 1. 4S investigator. Lancet 1994; 344: 1383-89, http://www.trialresultscenter.org/study2590-4S.htm;
2. HOPE investigator N Engl J Med 2000;342:145-53, http://www.trialresultscenter.org/study2606-HOPE.htm
EMPA-REG OUTCOME®:
Empagliflozin in type 2 diabetes on top of standard of care
leads to…
Benefits Risks

44 • Based on 1000 T2D patients receiving empagliflozin on top of standard of care for 3 years
 EMPA-REG OUTCOME
“Empagliflozin is the first of the recently approved diabetes
treatments associated with a lower risk of cardiovascular
disease.”

45
In the only SGLT-2 inhibitor cardiovascular outcomes trial
reported to date, empagliflozin was associated with
significantly lower rates of all-cause and cardiovascular death
and lower risk of hospitalization for heart failure

46
Unmet Medical Need: Complementary action

Showed significant Empagliflozin

RRR in myocardial
infarction and all Significantly lowered
cause mortality in CV risk and CV death
UKPDS.1 in EMPA-REG
OUTCOME study.2
Metformin

1. Holman R. Journ Annu Diabetol Hotel Dieu. 2007:13-20.

47 2. Ada 2016 Guidelines. Diabetes Care 2016;39(Suppl. 1):S60–S71
RRR: Relative Risk Reduction
Summary

1. CV disease is a leading cause of death in type 2 diabetes

patients.

2. Managing CV risk in T2D requires a multifactorial approach.

3. SGLT2 inhibitors modulate various factors related to CV risk.

4. Empagliflozin significantly lowered CV risk and death in T2D

patients at high CV risk in EMPA REG OUTCOME study.

5. Empagliflozin is the first of the recently approved diabetes

treatments associated with a lower risk of cardiovascular
disease.
48
 THANK YOU

49
CV safety of metformin

• Metformin is generally recommended as first-line therapy1,2

• Some evidence to suggest a CV benefit in overweight
patients1
• There remains a paucity of evidence from large, long-term,
placebo-controlled CV outcome trials3

1. http://www.medicines.org.uk/emc/medicine/23244/SPC. 2. American Diabetes Association. Diabetes Care

2015;38(suppl. 1):S1–S94. 3. Boussageaon et al. PLoS Med. 2012; 9:e1001204.

Met-
FOR INTERNAL USE ONLY, for-
50 DO NOT DETAIL OR DISTRIBUTE min