type 2 diabetes & cardiovascular disease: an update on current … · 2017. 1. 22. · pace cv...

Type 2 Diabetes & Cardiovascular Disease:An Update on Current and New strategies

for Improving Outcomes

Neil R PoulterInternational Centre for Circulatory Health &

Imperial Clinical Trials UnitImperial College London, UK

PACE CV Risk Master Class – Yogyakarta, Java – Indonesia 22 October 2016

Preventing Cardiovascular Events in

Patients with Diabetes

i. Intensifying all interventions

ii. Lipid lowering

iii.Blood pressure lowering

iv.Glycaemic control

T2Dm, Type 2 diabetes mellitus

Gaede P, et al. N Engl J Med 2003;348:383–393

• 160 patients with T2DM and microalbuminuria

• 80 patients allocated to conventional treatment

• 80 patients allocated to intensive treatment

• Mean age 55.1 years

• Mean follow-up 7.8 years

Steno Diabetes Centre

– Copenhagen, Denmark

The Steno-2 Study: A Summary

Can we reduce macrovascular events

in Type 2 diabetes?

Lipid lowering?(a)

21 (1.5%)

24 (1.7%)

51 (3.6%)

83 (5.8%)

Atorvastatin*

–48% (–69, –11)39 (2.8%)Stroke

–31% (–59, 16)34 (2.4%)Coronary revascularisation

–36% (–55, –9)77 (5.5%)Acute coronary events

–37% (–52, –17)

P=0.001127 (9.0%)Primary endpoint**

Hazard ratio Relative risk (CI)Placebo*Event

0.20.4 0.60.8 1 1.2

Favours atorvastatin Favours placebo

CARDS: Effects on major vascular events

*N (%) with an event

**Fatal MI, other acute CHD death, non-fatal MI, unstable angina, CABG, fatal stroke, non-fatal stroke

CABG, coronary artery bypass graft; CHD, coronary heart disease; CI, confidence interval; MI, myocardial infarction

Colhoun HM, et al. Lancet 2004;364:685–696

979 (10.5%)

3441 (9.6%)

4420 (9.8%)

627 (6.7%)

2807 (7.9%)

3434 (7.6%)

501 (5.4%)

1116 (3.2%)

1617 (3.7%)

1782 (19.2%)

6212 (17.4%)

7994 (17.8%)

Control

Effects on major vascular events of 1 mmol/L reduction

in LDL-C: Patients with and without diabetes from 14 RCTs

CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; RCT, randomised controlled trial; RR, relative risk

CTT Collaboration. Lancet 2008;371:117–125

Major vascular event

and prior diabetes

Major coronary event

Diabetes

No diabetes

Any major coronary event

Test for heterogeneity within subgroup: x21 = 0.1; p=0.8

Coronary revascularisation

Diabetes

No diabetes

Any Coronary revascularisation


Stroke

Diabetes

No diabetes

Any stroke


Major vascular event

Diabetes

No diabetes

Any major vascular event


1465 (15.6%)

4889 (13.7%)

6354 (14.1%)

407 (4.4%)

933 (2.7%)

1340 (3.0%)

491 (5.2%)

2129 (6.0%)

2620 (5.8%)

776 (8.3%)

2561 (7.2%)

3337 (7.4%)

Treatment

0.78 (0.69-0.87)

0.77 (0.73-0.81)

0.77 (0.74-0.80)

0.75 (0.64-0.88)

0.76 (0.72-0.81)

0.76 (0.73-0.80)

0.79 (0.67-0.93)

0.84 (0.76-0.93)

0.83 (0.77-0.88)

0.79 (0.72-0.86)

0.79 (0.76-0.82)

0.79 (0.77-0.81)

RR (CI)

0.5 0.0 1.5Treatment better Control better

Events (%)

RR (99% CI)

RR (95% CI)

Can we reduce macrovascular events in Type 2 diabetes?

YES

Lipid lowering(a)

Blood pressure lowering(b)

Among patients with Type 2 diabetes, blood pressure lowering was associated with improved mortality and other

clinical outcomesEffect of a 10 mmHg reduction in systolic blood pressure

Meta-analysis data based on 40 trials (N=100,354)

Outcome

No. ofstudies Events Participants

BP lowering

Events Participants

ControlRelative risk

(95% CI)Favours

BP loweringFavours control

Mortality

Cardiovascular disease

Coronary heart disease

Stroke

Heart failure

Renal failure

Retinopathy

Albuminuria

20

17

17

19

13

9

7

7

2334

3230

1390

1350

1235

596

844

2799

27,693

25,756

26,150

27,614

21,684

19,835

9781

13,804

2319

3280

1449

1475

1348

560

905

3163

25,864

24,862

24,761

26,447

20,791

18,912

9566

12,821

0.87 (0.78, 0.96)

0.89 (0.83, 0.95)

0.88 (0.80, 0.98)

0.73 (0.64, 0.83)

0.86 (0.74, 1.00)

0.91 (0.74, 1.12)

0.87 (0.76, 0.99)

0.83 (0.79, 0.87)

0.5 1.0 2.0

Relative risk (95% CI)

BP, blood pressure; CI, confidence interval

Emdin CA, et al. JAMA 2015;313:603–615

Patients

Guidelines Uncomplicated hypertension Diabetes Chronic renal failure

USA (JNC7 [2003]) <140/90 mmHg <130/80 mmHg <130/80 mmHg

USA (‘JNC8’ [2014]) <150/90 mmHg (60+ years) <140/90 mmHg <140/90 mmHg

<140/90 mmHg (<60 years)

ASH/ISH 2013 <150/90 mmHg (80+ years) <140/90 mmHg <140/90 mmHg

<140/90 mmHg

Europe (ESH 2013) <140/90 mmHg <140/85 mmHg <140/90 mmHg

China (CSH 2005) <140/90 mmHg

≤150 mmHg SBP for elderly)

<130/80 mmHg <130/80 mmHg

Russia <140/90 mmHg <130/80 mmHg <130/80 mmHg

Korea (KSH 2004) <140/90 mmHg <130/80 mmHg <130/80 mmHg

WHO-ISH (2003) SBP <140 mmHg <130/80 mmHg <130/80 mmHg

BHS IV 2004 <140/85 mmHg <130/80 mmHg <130/80 mmHg

Blood Pressure Targets

SBP, systolic blood pressure

CHEP (2014) <140/90 mmHg <130/80 mmHg <130/80 mmHg

Can we reduce macrovascular events

in Type 2 diabetes?

YES

Lipid lowering(a)

Blood pressure lowering(b)

Glucose lowering(c)

YES

EPIC-NORFOLK study (1995–2003): 4662 men (45–79 years)

HbA1c (%)

Event

CHD CV Death

<5.0 1.00 1.00 1.00

5.0– 1.56 1.23† 1.25†

5.5– 2.00 1.56 1.57

6.0– 2.13 1.79 1.80

6.5– 3.44 3.03 3.49

≥7.0 7.07 5.01 3.38

Known diabetes 4.82 3.32 3.68

Relative risks for cardiovascular events and deaths

†non-significant

CHD, coronary heart disease; CV, cardiovascular

Khaw KT, et al. Ann Int Med 2004;141:413–420

• Strength

• Dose response

• Temporal sequence

• Independence

• Consistency

• Coherence (plausible)

• Predictive

• Reversible

✓

✓

✓

✓

✓

✓

✓

?

From association to cause

How low?

Glucose Lowering

Intensive Glycaemic Control Increased

All-cause Mortality (ACCORD)

aMajor CV event: non-fatal MI, non-fatal stroke or cardiovascular death

CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction

ACCORD Study Group. N Engl J Med 2008;358:2545–2559

• Non-significant reduction in CV events in intensive group

(HR=0.90; P=0.16)

Primary outcomea

Mortality did not increase in other outcome trials

(e.g. VADT and ADVANCE)

• Increased mortality in intensive group

(HR=1.22; P=0.04)

Death from any cause

Standard therapy

Intensive therapy

Pati

en

ts w

ith

even

ts (

%)

25

20

15

10

5

00 1 2 3 4 5 6

Time (years)

Pati

en

ts w

ith

even

ts (

%)

25

20

15

10

5

00 1 2 3 4 5 6

Time (years)

• The latest outcomes trials investigating the effect

of intensive vs standard glucose control on CV

outcomes have not provided a clear answer

• The ADA has recently updated the recommended

target HbA1c from <6.5% to <7.0% for macrovascular

risk reduction

ADA, American Diabetes Association; CV, cardiovascular; HbA1c, glycated haemoglobin

ADA. Diabetes Care 2010;33(Suppl. 1):S11–S61

Glucose Lowering

With what and to whom?

Rosiglitazone was associated with a significant

increase in the risk of MI and with an increase in

the risk of death from CV causes that had

borderline significance.

Rosiglitazone – 2007

CV, cardiovascular; MI, myocardial infarction

Nissen SE, Wolski K. N Engl J Med 2007;356:2457–2471

“

”

Clinical Trial Results Scenarios and Likelihood

of Approvability

CI, confidence interval; HR, hazard ratio

Hirshberg B, Raz I. Diabetes Care 2011;34(Suppl. 2):S101–S106

Upper

limit of

95% CI

Non-inferiority

boundary

HR 1.8

Non-inferiority

boundary

HR 1.3

0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2.0 2.2

Hazard ratio

Superiority

Non-inferiority

Non-inferiority

Inferior

Under-powered

Approvable: No need

for post-marketing study

Approvable: Need

for post-marketing study

Not approvable

ALECARDIO(Aleglitazar, PPAR-αγ ) n=7226;

follow-up 2.0 yearsTermin. Q3 2013 – RESULTS

Insulin

20192015 20202013 2014 2016 2017 2018

PPAR-αγ

2021

SGLT2i

EMPA-REG OUTCOME(Empagliflozin, SGLT2i)

n=7000; duration up to 5 years Q2 2015 – RESULTS

CANVAS(Canagliflozin, SGLT2i)

n=4418; duration 4+ yearsCompletion Q2 2017

DECLARE-TIMI-58(Forxiga, SGLT2i)

n=17,276; duration ~6 yearsCompletion Q2 2019

CANVAS-R(Canagliflozin, SGLT2i)

n=5826; duration ~3 yearsCompletion Q1 2017

NCT01986881(Ertugliflozin, SGLT2i)

n=3900; duration ~6.3 yearsCompletion Q2 2020

CREDENCE (cardio-renal)(Canagliflozin, SGLT2i)

n= 3700; duration ~5.5 years Completion Q1 2020

DEVOTE(Insulin degludec, insulin)


GLP-1 RA

ELIXA(Lyxumia, GLP-1 RA)

n=6000; duration ~4 yearsQ1 2015 – RESULTS

FREEDOM (ITCA 650, GLP-1 RA in DUROS)


REWIND(Dulaglutide, QW GLP-1 RA)n=9622; duration ~6.5 years

Completion Q2 2019

SUSTAIN 6(Semaglutide, GLP-1 RA)

n=3297; duration ~2.8 yearsCompletion Q1 2016

LEADER(Victoza®, GLP-1 RA)

n=9341; duration 3.5–5 yearsCompletion Q4 2015

EXSCEL(Bydureon, QW GLP-1 RA)

n=14,000; duration ~7.5 yearsCompletion Q2 2018

HARMONY OUTCOME(Tanzeum, QW GLP-1 RA)

n~9400; duration ~4 yearsCompletion Q2 2019

DPP4i

TECOS(Januvia, DPP4i)

n=14,000; duration ~4–5 yearsQ4 2014 – RESULTS

SAVOR TIMI-53(Onglyza, DPP4i)

n=16,492; follow-up ~2 years Q2 2013 – RESULTS

EXAMINE(Nesina, DPP4i) n=5380;

follow-up ~1.5 yearsQ3 2013 – RESULTS

CAROLINA(Tradjenta, DPP4i vs SU)

n=6000; duration ~8 years Completion Q3 2018

CARMELINA(Tradjenta, DPP4i)

n=8000; duration ~4 years Completion Q1 2018

NCT01703208(Omarigliptin, QW DPP4i)


Cardiovascular outcomes trials

Boxes with broken lines are for completed CVOTs

CVOT, cardiovascular outcome trial; DPP4, dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium glucose co-transporter 2 inhibitor; SU, sulphonylurea

Source: clinicaltrials.gov (January 2015)

Recent CVOTs in T2DM

More of the same (adverse/no benefit):• ALECARDIO (Aleglitazar)• ACCORD (More or Less)• ORIGIN (Insulin vs. SC)• EXAMINE (Alogliptin)• SAVOR-TIMI (Saxagliptin)• TECOS (Sitagliptin)• ELIXA (Lixisenatide)

CVOT, cardiovascular outcomes trial; SC, standard care; T2DM, type 2 diabetes mellitus

Why do the cardiovascular outcome trials in Type 2

diabetes conflict with epidemiology-based expectations?

• Epidemiological association is not causal?

• Trial results wrong due to power/chance?

• Treating an aetiological factor does not necessarily

guarantee reversibility of effect

• Intervention too short and/or too small

• Wrong populations studied – e.g. too late

• Interventions cause other “off-target” damage

EMPA-REG Results

†Excluding silent MI.


Zinman B, et al. N Engl J Med 2015;373:2117–2128

Primary endpoint Death from cardiovascular causes

Death from any cause Hospitalisation for heart failure

Empagliflozin Placebo

HR 0.86

95% CI 0.74–0.99)

P=0.04 for superiority

HR 0.62

95% CI 0.49–0.77)

P<0.001

HR 0.68

95% CI 0.57–0.82

P<0.001

HR 0.65

95% CI 0.50–0.85

P=0.002

0 6 12 18 24 30 36 42 48

0

5

Month

10

15

20

Pa

tie

nts

wit

h e

ve

nt

(%)

0 6 12 18 24 30 36 42 48

Month

0

9

Pa

tie

nts

wit

h e

ve

nt

(%)

8

7

6

5

4

3

2

1

0 6 12 18 24 30 36 42 48

Month

0

5

10

15

Pa

tie

nts

wit

h e

ve

nt

(%)

Pa

tie

nts

wit

h e

ve

nt

(%)

0 6 12 18 24 30 36 42 48

Month

0

7

6

5

4

3

2

1

Time to first occurrence of CV death, non-fatal MI†, or non-fatal stroke

LEADER results

Marso et al. N Engl J Med 2016;375:311–22

HR=0.8795% CI (0.78–0.97)

p<0.001 from noninferiorityp=0.01 for superiority

Placebo

Liraglutide

Pati

en

ts w

ith

an

even

t (%

)

20

15

10

5

0

0 6 12 18 24 30 36 42 54

HR=0.7895% CI (0.66–0.93)

p=0.007

Placebo

LiraglutidePati

en

ts w

ith

an

even

t (%

)

20

10

0

0 6 12 18 24 30 36 42 54

15

5

HR=0.8595% CI (0.74–0.97)

p=0.02Placebo

Liraglutide

Pati

en

ts w

ith

an

even

t (%

)

20

10

5

0

0 6 12 18 24 30 36 42 54

HR=0.8795% CI (0.73–1.05)

p=0.14

Placebo

LiraglutidePati

en

ts w

ith

an

even

t (%

)

20

0

0 6 12 18 24 30 36 42 54

15

10

5

Primary endpoint Death from cardiovascular causes

Death from any cause Hospitalisation for heart failure

48 48

48 48

15


Nonfatal myocardial infarction

HR 0.74

95% CI 0.51–1.08

P=0.12

Weeks since randomization

Pa

tie

nts

with

eve

nt (%

)

No. at Risk

Placebo 1649 1624 1598 1587 1562 1542 1516

Semaglutide 1648 1623 1609 1595 1582 1560 1543

100

70

50

20

0

0 248 40 48 64 72 88 96 10916 32 56 80 104

90

80

60

40

30

10

5

1

00 248 40 48 64 72 88 96 10916 32 56 80 104

4

3

2

SUSTAIN 6 results

Marso SP et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1607141.

SemaglutidePlacebo

Primary outcome

HR 0.74

95% CI 0.58–0.95

P<0.001 for non-inferiority

P=0.02 for superiority


Pa

tie

nts

with

eve

nt (%

)

100

70

50

20

0

0 248 40 48 64 72 88 96 10916 32 56 80 104

90

80

60

40

30

10

10

7

5

2

00 248 40 48 64 72 88 96 10916 32 56 80 104

98

6

43

1

No. at Risk

Placebo 1649 1616 1586 1587 1534 1508 1479

Semaglutide 1648 1619 1601 1584 1568 1543 1524

Nonfatal stroke

HR 0.61

95% CI 0.38–0.99

P=0.04


Pa

tien

ts w

ith

eve

nt (%

) 100

70

50

20

0

0 248 40 48 64 72 88 96 10916 32 56 80 104

90

80

60

40

30

10

5

1

00 248 40 48 64 72 88 96 10916 32 56 80 104

4

3

2

No. at Risk

Placebo 1649 1629 1611 1597 1571 1548 1528

Semaglutide 1648 1630 1619 1606 1593 1572 1558

Death from cardiovascular causes

HR 0.98

95% CI 0.65–1.48

P=0.92


Pa

tie

nts

with

eve

nt (%

)

No. at Risk

Placebo 1649 1637 1623 1617 1600 1584 1566

Semaglutide 1648 1634 1627 1617 1607 1589 1579

100

70

50

20

0

0 248 40 48 64 72 88 96 10916 32 56 80 104

90

80

60

40

30

10

5

1

00 248 40 48 64 72 88 96 10916 32 56 80 104

4

3

2

Why/how did empagliflozin, liraglutide &

semaglutide work?

• Chance ?

• Glucose-lowering ?

• Blood pressure benefits ?

• Weight reduction ?

• Incipient heart failure ?

• Other(s) ?

1. Diet and lifestyle are the critical determinants of T2DM and merit

routine intervention

2. Treat those with T2DM with a statin (irrespective of lipid levels)

3. Treat those with T2DM with BP lowering (irrespective of BP level?)

4. Aspirin use for high-risk patients with T2DM?

5. Lower glucose in T2DM – microvascular benefits clear ± long-term

macrovascular benefits. Method of reduction matters

Conclusions

BP, blood pressure; T2DM, Type 2 diabetes mellitus

Meanwhile

• Huge and increasing medical, social and economic burden associated

with diabetes

• Developing countries are the worst affected

• Region-specific, targeted preventative strategies are urgently needed

• But for those already diagnosed – effective blood pressure and lipid lowering

are mandatory for macrovascular protection +/- empagliflozin and/or liraglutide

or semaglutide on top of usual care

type 2 diabetes & cardiovascular disease: an update on current … · 2017. 1. 22. · pace cv...

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