Diabetes: How to reduce risk from a

cardiovascular perspective?

Diederick E. Grobbee, MD, PhD, FESC

Professor of Clinical Epidemiology

President, European Association for Preventive Cardiology

Julius Center for Health Sciences and Primary Care

University Medical Center Utrecht, the Netherlands

0

1

2

3

CV death All-cause mortality

Haz

ard

rat

io (

95

% C

I) (

dia

bet

es

vs n

o d

iab

etes

)

Globally, 387 million people are living with diabetes1

At least 68% of people >65 years with diabetes die of heart disease2

This will rise to 592 million by 20351

1. IDF Diabetes Atlas 6th Edition 2014 http://www.idf.org/diabetesatlas; 2. Centers for Disease Control and Prevention 2011; 3. Seshasai et al. N Engl J Med 2011;364:829-41

Mortality risk associated with diabetes (n=820,900)3

3

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

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

OBESITY

Adiponectin

Adipocytokines

inflammatorycytokines*

T2D

Insulin resistance

Dyslipidaemia

Endothelial dysfunction

Hypertension

Age

Oxidative stress

Atherosclerosis

Interactions are complex, inter-related and not necessarily causal

4

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.

5

↓CV risk

Control of LDL-cholesterol

Antiplatelet therapy

Glycaemic control

Weight loss and lifestyle

intervention*

*Includes smoking cessation.Rydén et al. Eur Heart J 2013;34:3035–87.

Effects on macrovascular risk uncertain or not fully established

Effects on macrovascular risk established

Antihypertensive therapy

6

↓CV risk

Control of LDL-cholesterol

Antiplatelet therapy

Glycaemic control

Weight loss and lifestyle

intervention*

*Includes smoking cessation.

Antihypertensive therapy

<11

11-15

15-21

>21

0

10

20

30

40

50

60

70

1612

84

18

14

10

5

36

28

20

10

57

44

31

16

69

54

37

19CV

eve

nts

av

oid

ed p

er 1

00

0

7

Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet 2014;384:591–8.

Small BP reductions in high-risk individuals avoid as many events as large BP reductions in low-risk individuals

CV

eve

nts

av

oid

ed

per

10

00

8

↓CV risk

Control of LDL-cholesterol

Antiplatelet therapy

Glycaemic control

Weight loss and lifestyle

intervention*

*Includes smoking cessation.

Antihypertensive therapy

-32

-24 -23 -22-24

-31

-25

-44

-37

-8

-42

-19

-25

-18

-11

-60

-50

-40

-30

-20

-10

0

RR

red

uct

ion

or

haz

ard

rat

io (

%)

Combined

9

1. Ryden et al. Eur Heart J 2007;28:88–136. 2. Libby. J Am Coll Cardiol 2005;46:1225–8. 3. LaRosa et al. N Engl J Med 2005;352:1425–35. 4. Shepherd et al. N Engl J Med 1995;333:1301–8. 5. Downs et al. JAMA 1998;279:1615–22. 6. Ridker et al. N Engl J Med 2008;359:2195.7. Colhoun et al. Lancet 2004;364:685–96. 8. ALLHAT-LLT. JAMA 2002;288:2998–3007.

6605659520,536415990144444N 10,001 17,802

Non-diabetes Diabetes

AFCAPS/TexCAPS5

4S1,2 LIPID1,2 CARE1,2 WOSCOPS4Trial HPS1,2TNT3 JUPITER6

Secondary prevention Primary preventionHigh risk

CARDS7 ALLHAT-LLT8

2838 10,355

*Includes smoking cessation.

10

↓CV risk

Control of LDL-cholesterol

Antiplatelet therapy

Glycaemic control

Weight loss and lifestyle

intervention*

Antihypertensive therapy

1. Sarwar et al. Lancet 2010;375:2215–22.

2. Seshasai et al. N Engl J Med 2011;364:829–41.

Vascular death2

Ad

just

ed H

R (

95

% C

I)

2.5

2.0

03

1.5

0.9

4 100 5 6 7 8 9

Mean FBG concentration (mmol/L)

1.0

No history of diabetes at baselineHistory of diabetes at baseline

No known history of diabetes at baseline surveyKnown history of diabetes at baseline survey

Ad

just

ed H

R (

95

% C

I)

4.0

3.0

03

2.0

1.0

4 100 5 6 7 8 9

Mean FBG concentration (mmol/L)

Coronary heart disease1

VADT3UKPDS2

ADVANCE5

ACCORD4

1. Meinert et al. Diabetes 1970;19(suppl):789–830. 2. UKPDS 33. Lancet 1998;352:837–53. 3. Duckworth et al. N Engl J Med 2009;360:129–39. 4. Gerstein et al. N Engl J Med 2008;358:2545–59. 5. Patel et al. N Engl J Med 2008;358:2560–72.

12

1950 1960 1970 1980 1990 2000 2010

UGDP1

Date of first patient enrolment

*Median; †Mean.1. UKPDS 33. Lancet 1998;352:837–53. 2. Patel et al. N Engl J Med 2008;358:2560–72.3. Gerstein et al. N Engl J Med 2008;358:2545–59. 4. Duckworth et al. N Engl J Med 2009;360:129–39.

Trial NDuration

of follow-up (years)

Glycaemic target

Main inclusion criteriaIntensive treatment

Standard treatment

UKPDS1 3,867 10.0* FPG< 6 mmol/L

FPG< 15 mmol/L

T2D newly diagnosed

ADVANCE2 11,140 4.3* HbA1c

≤ 6.5%per local

guidelines

T2D and macrovascular or microvascular disease, or 1 CV risk factor

ACCORD3 10,251 3.5† HbA1c

< 6.0%HbA1c

7.0–7.9%T2D and CVD or 2 CV risk factors

VADT4 1,791 5.6* HbA1c

≤ 6%HbA1c

8–9%Long-standing, poorly controlledT2D

13

Myocardial infarction* p = 0.052 16%

Diabetes-related death* p = 0.3410%

All-cause mortality* p = 0.446%

0 10 20 30 40

Any diabetes-related endpoint* p = 0.02912%

Microvascular complications* p = 0.009925%

Retinopathy progression† p = 0.01521%

Microalbuminuria† p = 0.00005433%

Risk reduction (%)

14

*Median follow-up, 10 years; †assessed as surrogate endpoints; follow-up, 12 years.

UKPDS 33. Lancet 1998;352:837–53.

• Glucose lowering Sulfonylurea (gliclazide MR) based intensive therapy targeting HbA1c of 6.5% versus usual guideline-based care

• Blood pressure loweringFixed combination perindopril-indapamide versus matching placebo

• 2.0 / 0.625mg or placebo for first 3 months

• 4.0 / 1.25mg or placebo thereafter

N Engl J Med 2008;358:2560-72

Mean HbA1c (%)

5.0

5.5

6.0

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0

Follow-up (Months)

0 6 12 18 24 30 36 42 48 54 60 66

7.3 %

Mean HbA1c

at final visit

6.5%

Standard

Intensive

N Engl J Med 2008;358:2560-72

17

Patel et al. N Engl J Med 2008;358:2560–72.

Standard control Intensive control

Major microvascular eventsMajor macrovascular events

p = 0.3225

6

Cu

mu

lati

ve in

cid

ence

(%

)

20

15

10

5

018 24 30 36 42 48 66

Follow-up (months)

25

6

20

15

10

5

018 24 30 36 42 48

Follow-up (months)

p = 0.01

12 54 600 6612 54 600

14% risk reduction

N at Risk

Standard therapy 5109 4774 4588 3186 1744 455 436

Intensive therapy 5119 4768 4585 3165 1706 476 471

Gly

ca

ted

He

mo

glo

bin

(%

)

6.0

0 3 4 5

Years

0621

Standard TherapyIntensive Therapy

6.5

7.0

7.5

8.0

8.5

9.0

19

*First occurrence of non-fatal MI or non-fatal stroke or death from CV causes.

Gerstein et al. N Engl J Med 2008;358:2545–59.

Intensive therapy(n = 5128)

Standard therapy(n = 5123)

OutcomeNo. of patients

(annual event rate, %)No. of patients

(annual event rate, %)

Primary outcome* 352 (2.11) 371 (2.29)

Secondary outcome

Death

Any cause 257 (1.41) 203 (1.14)

CV cause 135 (0.79) 94 (0.56)

Non-fatal stroke 67 (0.39) 61 (0.37)

Fatal or non-fatal CHF 152 (0.90) 124 (0.75)

0.5 1.0 2.0

Hazard ratio (95% CI)

Favours intensive therapy

Favours standard therapy

Non-fatal MI 186 (1.11) 235 (1.45)

ADVANCE-ON

N Engl J Med 2014;371(15):1392-406

Zoungas et al. N Engl J Med 2014;371:1392-406.

22

Turnbull et al. Diabetologia 2009;52:2288–98.

Meta-analysis including 27,049 participants and 2370 major vascular events

0.5 1.0 2.0Hazard ratio (95% CI)

ACCORD 257 (1.41) 203 (1.14) -1.01ADVANCE 498 (1.86) 533 (1.99) -0.72UKPDS 123 (0.13) 53 (0.25) -0.66VADT 102 (2.22) 95 (2.06) -1.16Overall 980 884 -0.88

ACCORD 137 (0.79) 94 (0.56) -1.01ADVANCE 253 (0.95) 289 (1.08) -0.72UKPDS 71 (0.53) 29 (0.52) -0.66VADT 38 (0.83) 29 (0.63) -1.16Overall 497 441 -0.88

All-cause mortality

Cardiovascular death

Trials

Number of events(annual event rate, %)

More intensive Less intensive∆HbA1c (%)

Favours more intensive

Favours less intensive

Overall HR (95% CI)

1.04 (0.90–1.20)

1.10 (0.84–1.42)

23

Adapted from 1. Kirby. Br J Diabetes Vasc Dis 2012;12:315–20. 2. Lantus® SPC. FDA 2015.

1950 1960 1970 1980 1990 2000 2010 2012 2013

Lente class of insulins

produced

SUs first used

Metformin introduced in the UK

Recombinant human insulin

produced

2nd generation SUs available

Three new classes introduced: -glucosidase inhibitors, meglitinides

and TZDs

Glimepiride: 3rd generation SU

DPP4 inhibitors

GLP1 receptor agonists

SGLT2 inhibitors

Insulin degludec

Older T2D agents Newer T2D agents →

Insulin glargine available2

24

Timings represent estimated completion dates as per ClinicalTrials.gov.

Adapted from Johansen. World J Diabetes 2015;6:1092–96.

CANVAS-R8

(n = 5700)Albuminuria

2013 2014 2015 2016 2017 2018 2019

SAVOR-TIMI 531

(n = 16,492)1,222 3P-MACE

EXAMINE2

(n = 5380)621 3P-MACE

TECOS4

(n = 14,724)≥ 1300 4P-MACE

LEADER6

(n = 9340)≥ 611 3P-MACE

SUSTAIN-67

(n = 3297)3P-MACE

DECLARE-TIMI 5815

(n = 17,150)≥ 1390 3P-MACE

EMPA-REG OUTCOME®5

(n = 7034)≥ 691 3P-MACE

CANVAS10

(n = 4365)≥ 420 3P-MACE

CREDENCE17

(n = 3700)Renal + 5P-MACE

CAROLINA®11

(n = 6000)≥ 631 4P-MACE

ITCA CVOT9

(n = 4000)4P-MACE

EXSCEL14

(n = 14,000)≥ 1591 3P-MACE

DPP4 inhibitor CVOTs

SGLT2 inhibitor CVOTs

GLP1 CVOTsErtugliflozin CVOT18

(n = 3900)3P-MACE

OMNEON13

(n = 4000)4P-MACE

CARMELINA12

(n = 8300)4P-MACE + renal

REWIND16

(n = 9622)≥ 1067 3P-MACE

2021

ELIXA3

(n = 6068)≥ 844 4P-MACE

HARMONY Outcomes19

(n = 9400) 3P-MACE

26

SAVOR-TIMI 53

EXAMINE

HR: 1.0(95% CI: 0.89, 1.12)

HR: 0.96(95% CI: UL ≤1.16)

TECOSHR: 0.98

(95% CI: 0.88, 1.09)

ELIXAHR: 1.02

(95% CI: 0.89, 1.17)

DPP-4 inhibitors*

Lixisenatide

CV, cardiovascular; HR, hazard ratio; DPP-4, dipeptidyl peptidase-4*Saxagliptin, alogliptin, sitagliptinAdapted from Johansen OE. World J Diabetes 2015;6:1092-96

2013 2014 2015

28

1. Bakris et al. Kidney Int 2009;75;1272–7.

SGLT2SGLT2

inhibitor

SGLT1

SGLT2 inhibitors reduce glucose reabsorption

in the proximal tubule, leading to

urinary glucose excretion* and

osmotic diuresis

Filtered glucose load > 180 g/day

SNS activity (?)

29

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

Weight Visceral adiposity

Blood pressure Arterial

stiffness

Glucose Insulin

Albuminuria

Uric Acid

Novel Pathways (?)

LDL-C HDL-C

Triglycerides

Oxidative stress

SNS activity (?)

Zinman et al. Cardiovasc Diabetol 2014;13:102.

Placeborun-in

2 weeks

Empagliflozin 10 mg QD + usual care

Empagliflozin 25 mg QD + usual care

Placebo + usual care

Screening (n = 11,507)

Background therapy adjustment allowed after Week 12

12 weeks of stable background glucose-lowering therapy

Visit 1

Week

4 8 12 16 28 40 520-2-3

Visit 3 Visits 4–7every 4 weeks

Visits 8–10every 12 weeks

Visits every 14 weeks

Visit 2

Follo

w-u

p

R

End of study visit

+30 days

Aim Compound-specificTo determine CV safety of empagliflozin vs placebo + usual care for glycaemic control andCV risk in patients with T2D and high CV risk

6,0

6,5

7,0

7,5

8,0

8,5

9,0

Ad

just

ed m

ean

(SE

) H

bA

1c

(%)

Week

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

2294

2296

2296

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

2272

2272

2280

2188

2218

2212

2133

2150

2152

2113

2155

2150

2063

2108

2115

2008

2072

2080

1967

2058

2044

1741

1805

1842

1456

1520

1540

1241

1297

1327

1109

1164

1190

962

1006

1043

705

749

795

420

488

498

151

170

195

12 28 52 94 10880 12266 1360 150 164 178 192 20640

All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat) X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

HR 0.86(95.02% CI 0.74, 0.99)

p=0.0382*

Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)

HR 0.68(95% CI 0.57, 0.82)

p<0.0001

Kaplan-Meier estimate. HR, hazard ratio

• Type II Diabetes is a major determinant of cardiovascular risk

• While improvements in care and effective treatments large unmet medical need remains

• BP and lipid lowering and antiplatelets essential elements of prevention

• Benefits of strict glucose control debated for macrovascular disease

• First results of SGLT2 inhibition look promising as an add-on treatment in type II diabetes

• GLP-1 agonists new kid on the block with new potential?