pccs diabetes and the heart kdm ndm ifg igt ngt ausdiab = australian diabetes, obesity, and...

PCCS Diabetes and the Heart

Professor Mike Kirby FRCP

Evolution of diabetes management

1950 1960 1970 1980 1990 2000

Lente

class of

insulins

introduced

Sulphonylureas

first used in UK

Metformin

available in

UK

Injection

guns

available

SMBG

meters

introduced

in the UK

Monocomponent

insulin developed

Disposable

plastic

syringes

developed

Recombinant

human

insulin

produced

Computerised

SMBG

devices

developed

Changes to

GP contracts

for chronic

disease

management

DCCT UKPDS

2nd generation

sulphonylureas

available

Some insulin

pens included

on NHS

prescription list

NSF for Diabetes

followed by NICE

guidance in 2008

CSII pumps

Insulin

aspart &

lispro

developed

Three new classes of

OADs introduced:

-glucosidase

inhibitors, meglitinides

& thiazolidinediones

Glimepiride

- 3rd

generation

sulphonylurea

New

Designer

insulins

First shared

care scheme

tried

GLP-1

receptor

agonists

2010

DPP4

inhibitor

s

2012

SGLT2

inhibitors

Insulin

degludec

+ others

Unadjusted Mortality According to Glucose Metabolism: Data from AusDiab

Cum

ula

tive I

ncid

ence o

f All-c

ause M

ort

ality

Time (years)

Reprinted from Barr EL, et al. Circulation. 2007;116:151–157, with permission from Lippincott Williams & Wilkins.

0.00

0.05

0.10

0.15

0 2 6 4

All-Cause Mortality

KDM

Cum

ula

tive I

ncid

ence o

f CVD

Mort

ality

Time (years)

0.00

0.01

0.02

0.03

0.04

0.05

0 2 6 4

CVD Mortality

NDM

IGT

IFG NGT

KDM

NDM

IFG

IGT

NGT

AusDiab = Australian Diabetes, Obesity, and Lifestyle Study; CVD = cardiovascular;

KDM = known diabetes mellitus; NDM = newly diagnosed diabetes mellitus; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; NGT = normal glucose tolerance

Multifactorial intervention benefits diabetes and CV outcomes: STENO-2 study

Gaede P et al. New Eng J Med 2003; 348: 383–93

0

20

40

60

Pati

en

t w

ith

pri

mary

co

mp

osit

e e

nd

po

int

(%)

Conventional therapy Multifactorial intervention

96 72 48 24 0

Follow-up (months)

p=0.007

Multifactorial intervention = stepwise implementation of behaviour modification,

pharmacological therapy targeting hyperglycaemia, hypertension, dyslipidaemia and

microalbuminuria

20% Absolute risk reduction in CVD

53% RR reduction in CVD 60% RR reduction in

microvascular complications

N=160

Kaplan-Meier estimates of the composite end points Death from CV causes: non-fatal MI, CABG, angioplasty, non-fatal stroke, amputation or surgery for PVD

How do we modify CV risk in T2D?1–3

Lifestyle modification

Glycaemic control

Multifactorial approach

Blood pressure control

Platelet inhibition

Management of dyslipidaemia

CV, cardiovascular; T2D, type 2 diabetes.

1. Rydén L et al; Eur Heart J. 2013; 34: 3035–3087; 2. Fox CS et al; Diabetes Care. 2015; 38: 1777–1803; 3. Piepoli MF et al; Eur Heart J. 2016; 37: 2315–2381.

What percentage of people registered with diabetes achieved the NICE

defined treatment targets for glucose control, blood pressure and blood

cholesterol?

Type 1 Type 2 and other

2009-10 2010-11 2011-12 2012-13 2013-14 2014-15 2009-10 2010-11 2011-12 2012-13 2013-14 2014-15

HbA1c < 58 mmol/mol 28.7 28.1 27.0 27.2 29.4 29.9 66.6 66.5 65.8 64.9 66.8 66.1

Blood Pressure < 140/80* 68.5 68.8 72.2 73.4 76.4 76.4 60.8 61.4 66.6 68.6 73.6 74.2

Cholesterol < 5mmol/L 72.6 72.0 71.1 70.2 71.5 71.3 78.2 78.0 77.4 76.7 77.8 77.5

Meeting all three treatment targets 16.9 16.5 16.5 16.1 18.6 18.9 35.0 35.1 37.4 37.3 41.4 41.0

Percentage of people with diabetes in England and Wales achieving their treatment

targets by diabetes type and audit year

* The blood pressure target does not exactly match NICE (<140/80) but was changed to align with the relevant QOF indicator (<140/80) . More information can be found here

https://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwiJnJzMzdDPAhXB2hoKHT6IA-IQjRwIBw&url=https://mohdarafat.wordpress.com/tag/mohdarafat/&psig=AFQjCNHcztETFbFwHxVMw4w2YeCHJhRakw&ust=1476201560196929

http://www.hscic.gov.uk/media/14985/Methodological-change-2014-NDA-Report-Care-Processes-and-Treatment-TargetsMethodology-Paper1-0/pdf/Methodological_change_-_NDA_Report_Care_Processes_and_Treatment_Targets_Methodology_Paper1_0_2014.pdf

Lower rates of

diabetes-

related

complications

in the US

The cost of treating diabetes complications outweighs drug

acquisition costs The following table represents the relative cost of diabetes treatment in the UK in 20101

Area of expenditure Type 1

diabetes

T2DM Total

cost

Percentage of costs

Diabetes drugs £0.344 billion £0.712 billion £1.056 billion 7.8%

Non-diabetes drugs £0.281 billion £1.810 billion £2.091 billion 15.2%

Inpatient £1.007 billion £8.038 billion £9.045 billion 65.8%

Outpatient

(excluding drugs)

£0.170 billion £1.158 billion £1,328 billion 9.7%

Other (including

social service)

- - £0.230 billion 1.7%

Total £1.802 billion £11.718 billion £13.750 billion 100%

1. Kanavos, van den Aardweg and Schurer: Diabetes expenditure, burden of disease and

management in 5 EU countries, LSE (Jan 2012); 2. Hex et al. Diabet Med. 2012 Jul;29(7):855-62

2035 / 20362

T2DM direct costs £15.1bn

T2DM indirect costs £20.5bn

17% total health expenditure

2010 / 20112

T2DM direct costs £8.8bn

T2DM indirect costs £13bn

10% total health expenditure

Taking a “Vascular” approach

• New policy embracing – Stroke

– CHD

– Diabetes

– Renal disease

• Shared agenda – Prevention

– Awareness raising

– Risk management

• Many patients experience multiple conditions

Outline

• So what’s new?

• 2016/17 guidelines

• How & why to combine therapies

• Emerging cardiovascular benefits of newer

diabetes therapies

CVD is the leading cause of death in people with diabetes*

CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; MI, myocardial infarction; T1D, type 1 diabetes; T2D, type 2 diabetes.

1. Emerging Risk Factors Collaboration; N Engl J Med. 2011; 364: 829–841; 2. Centers for Disease Control and Prevention. National diabetes fact sheet, 2011. CDC website; 2011. Available from: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf [Accessed March 2017]; 3. International Diabetes Federation. IDF Diabetes Atlas, 7th edn. Brussels, Belgium: IDF, 2015. Available from: http://www.diabetesatlas.org [Accessed March 2017]; 4. Burgess DC et al; Eur Heart J. 2010; 31: 92–99.

0

1

2

3

CV death All-cause mortality

Haz

ard

rat

io (

95

% C

I) (

dia

bet

es v

s. n

o

dia

bet

es)

Mortality risk associated with diabetes* (n=820,900)1

0

7

6

5

4

3

2

1

0

40 50 60 70 80 90

Age (years)

Year

s o

f lif

e lo

st

Men

7

6

5

4

3

2

1

0

40 50 60 70 80 90 0

Age (years)

Women

Non-vascular deaths

Vascular deaths Heart disease was noted in more than two-thirds of diabetes-related deaths among

people aged 65 years or older (T1D and T2D data combined)2

Years of life lost in people with diabetes* compared with non-diabetes peers1

In high-income countries, up to 91% of adults with diabetes have T2D3

36.8% of all MIs in patients with T2D were found to be silent in the FIELD study (n=9,795), which is within the reported range of silent MIs (22–40%)4

*Information on diabetes type (i.e., type 1 or 2) was not available, although the age of the participants suggests that the large majority with diabetes would have type 2.

More vs. less-intensive glycaemic control MACE, MI, all-cause mortality

ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular disease: Preterax and Diamicron modified release Controlled Evaluation; CI, confidence interval; HbA1c, glycated haemoglobin; MACE, major adverse cardiovascular event; MI, myocardial infarction; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.

Adapted from: Turnbull FM et al; Diabetologia. 2009; 52: 2288–2298.

n events (annual event rate, %)

0.5 2.0 1.0

Hazard ratio (95% CI)

Hazard ratio (95% CI) Trials

More intensive

Less intensive

ΔHbA1c

(%)

Favours more intensive

Favours less intensive

Myocardial infarction ACCORD ADVANCE UKPDS VADT Overall

198 (1.18) 310 (1.18) 150 (1.20) 72 (1.65) 730

245 (1.51) 337 (1.28) 76 (1.40) 87 (1.99) 745

-1.01 -0.72 -0.66 -1.16 -0.88

0.77 (0.64; 0.93) 0.92 (0.79; 1.07) 0.81 (0.62; 1.07) 0.83 (0.61; 1.13) 0.85 (0.76; 0.94) (Q=2.25, p=0.52, I2=0.0%)

0.90 (0.78; 1.04) 0.94 (0.84; 1.06) 0.80 (0.62; 1.04) 0.90 (0.70; 1.16) 0.91 (0.84; 0.99) (Q=1.32, p=0.72, I2=0.0%)

Major cardiovascular event ACCORD ADVANCE UKPDS VADT Overall

352 (2.11) 557 (2.15) 169 (1.30) 116 (2.68) 1,194

371 (2.29) 590 (2.28) 87 (1.60) 128 (2.98) 1,176

-1.01 -0.72 -0.66 -1.16 -0.88

1.22 (1.01; 1.46) 0.93 (0.83; 1.06) 0.96 (0.70; 1.33) 1.07 (0.81; 1.42) 1.04 (0.90; 1.20) (Q=5.71, p=0.13, I2=47.5%)

All-cause mortality ACCORD ADVANCE UKPDS VADT Overall

257 (1.41) 498 (1.86) 123 (0.13) 102 (2.22) 980

203 (1.14) 533 (1.99) 53 (0.25) 95 (2.06) 884

-1.01 -0.72 -0.66 -1.16 -0.88

ACCORD VADT ADVANCE

p< 0.01 p<0.001 p<0.001

Severe Hypoglycemic episodes

in ACCORD, VADT, ADVANCE

CRP, C-reactive protein; IL-6, interleukin 6; VEGF, vascular endothelial growth factor

Desouza et al. Diabetes Care 2010;33:1389–94

Pathophysiological cardiovascular consequences of hypoglycaemia

UKPDS=United Kingdom Prospective Diabetes Study

Holman RR et al (2008) N Engl J Med 359: 1577–89 UKPDS Group (1998) Lancet 352: 854–65

Me

dia

n H

bA

1c (

%)

0

6

7

8

9

UKPDS 1998

Conventional Approach

More intensive approach

Holman et al 2008

Drives the “legacy effect”

1997

Difference in HbA1c was lost after first year but those in the initial

intensive arm still had lower incidence of any complication 10 years

later (the legacy effect):

• 21% reduction in any diabetes-related endpoint (P=0.01)

• 33% reduction in myocardial infarction (P=0.005)

• 27% reduction in death from any cause (P=0.002)

2007

UKPDS: early, intensive control of

hyperglycaemia is important

Long-term effects of intensive diabetes treatment

ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular disease: Preterax and Diamicron modified release Controlled Evaluation; CVD, cardiovascular disease; DCCT/EDIC, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.

1. UKPDS Group; Lancet. 1998; 352: 854–865; 2. Holman RR et al; N Engl J Med. 2008; 359: 1577–1589; 3. DCCT Research Group; N Engl J Med. 1993; 329; 977–986; 4. Nathan DM et al; N Engl J Med. 2005; 353: 2643–2653; 5. DCCT/EDIC Research Group; JAMA. 2015; 313: 45–53; 6. ACCORD Study Group; N Engl J Med. 2008; 358: 2545–2559; 7. ACCORD Study Group; Diabetes Care. 2016; 39: 701–708; 8. ACCORDION Eye Study Group, ACCORDION Study Group; Diabetes Care. 2016; 39: 1089–1100; 9. ADVANCE Collaborative Group; N Engl J Med. 2008; 358: 2560–2572; 10. Duckworth W et al; N Engl J Med. 2009; 360: 129–139; 11. Hayward RA et al; N Engl J Med. 2015; 372: 2197–2206.

Study Microvascular CVD Mortality

UKPDS1,2 ↓ ↓ ↔ ↓ ↔ ↓

DCCT/EDIC3–5 ↓ ↓ ↔ ↓ ↔ ↓

ACCORD6–8 ↓ ↓ ↔ ↑ ↔

ADVANCE9 ↓ ↔ ↔

VADT10,11 ↔ ↔ ↓ ↑ ↔

Initial trial Long-term follow up

The rosiglitazone experience

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

“Rosiglitazone was associated with a

significant increase in the risk of myocardial infarction and with an increase in the risk of

death from cardiovascular causes

that had borderline significance.”

The advantages and limitations of CVOTs1,2

CV, cardiovascular; CVOTs, cardiovascular outcome trials.

1. Hirshberg B, Raz A; Diabetes Care. 2013; 36(Suppl. 2): S253–S258; 2. Schnell O et al; Cardiovasc Diabetol. 2016; 15: 139.

Pros Cons

• Trials include patients with high CV risk

• The trials will generate large volumes of long-term data for analysis

• CV tolerability data are important for diabetes therapies

• Long-term efficacy data from blinded, randomised trials

• Non-CV tolerability data

• Identifying rare events

• Generalisability of results to all populations may be limited

• Non-CV specific endpoint data may be of limited value

• Trials are not designed to document glycaemic control, body weight, etc.

• Wide range of concomitant medications

• Development costs increase • Larger and longer phase 3

programmes

• Reduced incentive for development of new drugs

• Development limited to larger companies

Advantages Limitations

Cardiovascular outcome trials

*Also known as C-SCADE-8. ** An interim was completed in Q4 2016, but did not meet predefined stopping rules and continues to completion in Q3 2018 ***According to company information two interims are planned in 2016 and 2017, respectively (1/3 and 2/3 of total events). Completion date is the estimated completion date for the primary outcomes measure. Full abbreviations in speaker notes. Source: Competitive Intelligence Diabetes; Company information.

2013 2014 2015 2016 2017 2018 2019 2020

Pre-approval Pre+post-approval Post-approval Other Terminated

TECOS (Januvia, DPP-4i)

n=14,671; follow-up ~3 yrs Q1 2015 - NEUTRAL

CARMELINA (Tradjenta, DPP-4i)

n= 8,300; duration ~4 yrs completion Q1 2018

CAROLINA (Tradjenta, DPP-4i vs SU) n= 6,115; duration ~8 yrs

completion Q1 2019

SAVOR TIMI-53 (Onglyza, DPP-4i)

n=16,492; follow-up ~2 yrs Q2 2013 – NEUTRAL

EXAMINE (Nesina, DPP-4i) n=5,380; follow-

up ~1.5 yrs Q3 2013 – NEUTRAL

ALECARDIO (Aleglitazar, PPAR-αγ) n=7,226;

follow-up 2.0 yrs Termin. Q3 2013 - RESULTS

LEADER (Victoza®, GLP-1)

n=9,340; follow up 3.5-5 yrs Q1 2016 -

SUPERIOR

ELIXA (Lyxumia, GLP-1)

n=6,076; follow-up ~2 yrs Q1 2015 – NEUTRAL

EMPA-REG OUTCOME* (Empagliflozin, SGLT2i)

n=7,020; follow-up~3 yrs

Q2 2015 – SUPERIOR

SUSTAIN 6 (Semaglutide, GLP-1) n=3,297; FU ~2.8 yrs

Q1 2016 Sig. Reduc.

EXSCEL (Bydureon, QW GLP-1) n=14,000; dur. ~7.5 yrs

Q2 2017- NEUTRAL

CANVAS-R (Canagliflozin, SGLT2i)

n=5,840; duration ~3 yrs

Q1 2017– SUPERIOR

DEVOTE (Tresiba®, insulin degludec)

n=7,637; duration up to 5yrs Q3 2016 - NEUTRAL

FREEDOM-CVO (ITCA 650, GLP-1 in DUROS) n=4,000; follow-up ~1.2 yrs

Q2 2016 - NEUTRAL

CREDENCE (cardio-renal) (Canagliflozin, SGLT2i)

n= 4,200; duration ~5.5 yrs completion Q1 2019

REWIND** (Dulaglutide, QW GLP-1)

n=9,622; duration ~6.5yrs completion Q3 2018

DECLARE-TIMI-58*** (Dapagliflozin, SGLT2i)

n=17,276; duration~6 yrs completion Q2 2019

VERTIS CV (Ertugliflozin, SGLT2i)

n=8,000; duration~6.1 yrs completion Q4 2019

HARMONY OUTCOMES (Albiglutide, GLP-1)

n=9,400; duration ~4yrs completion by Q2 2019

PIONEER 6 (Oral Semaglutide, GLP-1)

n=3,176; dur. ~19 mths completion Q2 2018

CANVAS (Canagliflozin, SGLT2i)

n=4,431; duration 4+yrs

Q1 2017– SUPERIOR

Superior Significant Reduction

Aleglitazar and semaglutide are not licensed for use. Liraglutide and Canagliflozin are not indicated for CV risk reduction. Semaglutide (subcutaneous and oral forms) and ertugliflozin have been submitted for market authorisation and are awaiting approval.

The Truth Is Not So Sweet

Cardiovascular safety of diabetes drugs

• The goal of merely lowering

blood glucose levels in

diabetes is too simplistic

• With respect to CVD it appears

important how you lower blood

sugar as well as how much

• Diabetes drugs, even within

the same “class” may yield

dramatically different CV

outcomes

http://www.escardio.org/

Common components of MACE in CVOTs

CV, cardiovascular; CVOTs, cardiovascular outcome trials; MACE, major adverse cardiovascular event.

• CVOTs commonly have as their primary outcomes a composite endpoint of major adverse CV events (MACE)

– The majority are composed of three CV events

– Some are composed of four CV events

Unstable angina requiring hospitalisation

CV death Myocardial infarction Stroke

EMPA-REG OUTCOME®: primary endpoint

CV death, non-fatal MI or non-fatal stroke

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; No. number.

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

No. at risk:

Empagliflozin 4,687 4,580 4,455 4,328 3,851 2,821 2,359 1,534 370

Placebo 2,333 2,256 2,194 2,112 1,875 1,380 1,161 741 166

Empagliflozin (10.5%)

Placebo (12.1%)

Month

0 6 12 18 30 24 42 36 48

20

10

5

0

15

Patients

with e

vent

(%)

Incidence rate empagliflozin vs. placebo: 37.4 vs. 43.9 events/1,000 patient-years

HR: 0.86 (95% CI: 0.74; 0.99)

p=0.04 for superiority

Month 0 6 12 18 30 24 42 36 48

20

10

5

0

15

Patients

with e

vent

(%)

HR:0.86 (95% CI: 0.74; 0.99) p=0.04 for superiority

CV death, non-fatal MI or non-fatal stroke

0 6 12 18 30 24 42 36 48

Patients

with e

vent

(%)

9

7

6

0

8

5

3

2

4

1

Month

HR: 0.62 (95% CI: 0.49; 0.77)

p<0.001

Death from CV causes

0 6 12 18 30 24 42 36 48

Patients

with e

vent

(%) 7

6

0

5

3

2

4

1

Month

HR: 0.65 (95% CI: 0.50; 0.85)

p=0.002

Hospitalisation for heart failure

0 6 12 18 30 24 42 36 48

Patients

with e

vent

(%)

15

10

0

5

HR: 0.68 (95% CI: 0.57; 0.82)

p<0.001

Month

Death from any cause

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.


EMPA-REG OUTCOME®: primary endpoint Individual components

EMPA-REG OUTCOME®: microvascular outcomes

Endpoint Empagliflozin

n/N (%)

Placebo n/N (%)


p value

New or worsening nephropathy* 525/4,124

(12.7) 388/2,061

(18.8) 0.61

(0.53; 0.70) <0.001

New onset of macroalbuminuria 459/4,091

(11.2) 330/2,033

(16.2) 0.62

(0.54; 0.72) <0.001

Doubling of serum creatinine† 70/4,645 (1.5)

60/2,323 (2.6)

0.56 (0.39; 0.79)

<0.001

Initiation of renal replacement therapy

13/4,687 (0.3)

14/2,333 (0.6)

0.45 (0.21; 0.97)

0.041

Death due to renal disease‡ 3/4,687 (0.1)

0/2,333 (0)

– –

*Composite of new onset of macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy, or death due to renal disease.

†Accompanied by eGFR (MDRD) ≤45 ml/min/1.73m2. ‡Hazard ratio and 95% CI were not analysed as the total number of events was <14.

CI, confidence interval; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease.

Wanner C et al; Diabetes. 2016; 65(Suppl 1): Abstract and poster 1086-P.

Empagliflozin is not licensed for treatment of renal impairment or nephroprotection.

• Empagliflozin used in addition to standard care reduced the risk of a composite microvascular outcome in patients with T2D and high CV risk

– Standard care included approximately 80% of patients on ACE inhibitors/ARBs, 77% on statins and 83% on acetylsalicylic acid at baseline

• Risk reduction was primarily driven by a reduction in incident or worsening nephropathy with empagliflozin compared to placebo

• Eye-related outcomes were rare in both groups

EMPA-REG OUTCOME®: microvascular outcomes

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; CV, cardiovascular; T2D, type 2 diabetes.

Wanner C et al; Diabetes. 2016; 65(Suppl. 1): Abstract and poster 1086-P.


EMPA-REG OUTCOME®: summary of clinical and metabolic outcomes

HbA1c Weight

sBP dBP

dBP, diastolic blood pressure; HbA1c, glycated haemoglobin; sBP, systolic blood pressure; SE, standard error. Zinman B et al; N Engl J Med. 2015; 373: 2117–2128.

• EMPA-REG OUTCOME® demonstrated superiority for MACE (CV-death, non-fatal MI and non-fatal stroke) with empagliflozin treatment vs. placebo

– The incidence of the composite MACE endpoint was 37.4 events/1,000 patients-years with empagliflozin compared with 43.9 events/1,000 patient-years with placebo

– HR corresponding to an estimated risk reduction for MACE of 14% was observed

• 10.5% of patients in the empagliflozin group vs. 12.1% of patients in the placebo group: HR=0.86 (95% CI: 0.74; 0.99); p=0.04 for superiority

– CV death and non-fatal MI components of MACE contributed to the risk reduction

• Empagliflozin used in addition to standard of care reduced the risk of a composite microvascular outcome in patients with T2D and high CV risk

– Risk reduction was primarily driven by a reduction in incident or worsening nephropathy with empagliflozin compared to placebo

EMPA-REG OUTCOME®: summary

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major cardiovascular adverse events; MI, myocardial infarction; T2D, type 2 diabetes.



Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk

28

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

Simvastatin1

for 5.4 years

High CV risk 5% diabetes, 26% hypertension

1994 2000 2015

Pre-statin era

High CV risk 38% diabetes, 46% hypertension

Ramipril2

for 5 years

Pre-ACEi/ARB era

<29% statin

Empagliflozin for 3 years

T2DM with high CV risk 92% hypertension

>80% ACEi/ARB

>75% statin

http://www.trialresultscenter.org/study2590-4S.htm




http://www.trialresultscenter.org/study2606-HOPE.htm





CANVAS program: primary endpoint

Intent-to-treat analysis. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular events. Adapted from: Neal B et al; New Engl J Med. 2017; doi:10.1056/NEJMoa1611925.

HR: 0.86 (95% CI: 0.75; 0.97)

Non-inferiority: p<0.001 Superiority: p=0.02

31.5 /1,000 patient-years

26.9 /1,000 patient-years

Canagliflozin is not indicated for cardiovascular risk reduction.

3-point MACE: CV death, non-fatal myocardial infarction or non-fatal stroke

n based on all patients correctly randomised. *Includes death from CV causes, non-fatal myocardial infarction and non-fatal stroke; †Canagliflozin (n=5,196), placebo (n=3,819). CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; MACE, major adverse cardiovascular events. Adapted from: Neal B et al; N Engl J Med. 2017; doi:10.1056/NEJMoa1611925; Matthews DR et al; ADA 2017; Symposium presentation 3-CT-SY26.

Outcome

Canagliflozin (n=5,795)

Placebo (n=4,347) Hazard ratio (95% CI)

Event rate per 1,000 patient-years

3-point MACE* 26.9 31.5 0.86 (0.75; 0.97)

Death from CV causes 11.6 12.8 0.87 (0.72; 1.06)

Non-fatal myocardial infarction 9.7 11.6 0.85 (0.69; 1.05)

Non-fatal stroke 7.1 8.4 0.90 (0.71; 1.15)

Hospitalisation for heart failure 5.5 8.7 0.67 (0.52; 0.87)

Death from CV causes or hospitalisation for heart failure

16.3 20.8 0.78 (0.67; 0.91)

Death from any cause 17.3 19.5 0.87 (0.74; 1.01)

Progression of albuminuria† 89.4 128.7 0.73 (0.67; 0.79)

40% reduction in eGFR, renal-replacement therapy or renal death

5.5 9.0 0.60 (0.47; 0.77)

Favours placebo

CANVAS program: CV, renal, hospitalisation and death events

1.0

Favours canagliflozin

2.0 0.5

Canagliflozin is not indicated for cardiovascular risk reduction. Canagliflozin is not indicated for renal protection or treatment of renal impairment.

CANVAS program: metabolic outcomes

Mixed model for repeated measures analysis. CI, confidence interval; HbA1c, glycated haemoglobin.

Adapted from: Neal B et al; N Engl J Med. 2017; doi:10.1056/NEJMoa1611925; Matthews DR et al; ADA 2017; Symposium presentation 3-CT-SY26.

(n=4245) Mean difference: −1.60 kg

(95% CI: −1.70; −1.51)

Weight HbA1c

Mean difference: −0.58% (95% CI: −0.61; −0.56)

p<0.001

• Patients with T2D who had an increased risk of CV disease, treated with canagliflozin compared to placebo had a significantly lower risk of:

– Death from CV causes, non-fatal myocardial infarction or non-fatal stroke

• Incidence rate of canagliflozin vs. placebo: 26.9 vs. 31.5 events/100 patient-years

• HR: 0.86 (95% CI: 0.75; 0.97), p<0.001

– Hospitalisation for heart failure

• Incidence rate of canagliflozin vs. placebo: 5.5 vs. 8.7 events/100 patient-years

• HR: 0.67 (95% CI: 0.52; 0.87)

– Renal complications, specifically progression of albuminuria, and 40% reduction in eGFR, renal-replacement therapy or renal death

• Adverse events were similar across treatment arms, with the exception of amputation risk which was increased in the canagliflozin cohort

CANVAS program: summary

*Significant difference between treatment groups (p<0.05). P values estimated from Cox regression models; **Canagliflozin (n=5,790), placebo (n=4,344), analysis based on those that received ≥1 dose of drug or placebo. CI, confidence interval; CV, cardiovascular; HbA1c.glycated haemoglobin; HR, hazard ratio; MACE, major adverse cardiovascular events; T2D, type 2 diabetes. Adapted from: Neal B et al; N Engl J Med. 2017; doi:10.1056/NEJMoa1611925; Matthews DR et al; ADA 2017; Symposium presentation 3-CT-SY26.

Canagliflozin is not indicated for cardiovascular risk reduction. Canagliflozin is not indicated for renal protection or treatment of renal impairment.

LEADER: primary outcome CV death, non-fatal MI, or non-fatal stroke

The primary composite outcome in the time-to-event analysis was the first occurrence of death from CV causes, non-fatal MI, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months.

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.

Marso SP et al; N Engl J Med. 2016; 375: 311–322.

0 6 18 24 30 36 42 48 54 0

5

10

15

20

12

Incidence rate of liraglutide vs. placebo: 3.4 vs. 3.9 events/100 patient-years

Time from randomisation (months)

Liraglutide

Placebo

4,668

4,672

4,593

4,588

4,496

4,473

4,400

4,352

4,280

4,237

4,172

4,123

4,072

4,010

3,982

3,914

1,562

1,543

424

407

Patients at risk

Liraglutide

Placebo

Patients

with a

n e

vent

(%)

Liraglutide is not indicated for cardiovascular risk reduction.

HR: 0.87 (95% CI: 0.78; 0.97)

p<0.001 for non-inferiority; p=0.01 for superiority

Hazard ratio (95% CI) p value

Liraglutide Placebo

n % R n % R

Number of patients 4,668 100.0 4,672 100.0

CV death 0.78 (0.66; 0.93) 0.007 219 4.7 1.2 278 6.0 1.6

Non-fatal MI 0.88 (0.75; 1.03) 0.11 281 6.0 1.6 317 6.8 1.8

Non-fatal stroke 0.89 (0.72; 1.11) 0.30 159 3.4 0.9 177 3.8 1.0

LEADER: individual components of the primary endpoint

Hazard ratios and p values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate.

%, percentage of group; CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; n, number of patients; R, incidence rate per 100 patient-years of observation.



Favours placebo Favours liraglutide

10 .5 1 .5


*The cumulative incidences were estimated using the Kaplan–Meier method, and the hazard ratios using the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, as less than 10% of patients had an observation time beyond 54 months. **Full analysis set. The cumulative incidences of time to EAC-confirmed first hospitalisation for heart failure or all-cause death were estimated using the Kaplan–Meier method, and the hazard ratios using the Cox proportional-hazard regression model. The data analyses are truncated at 48 months, as less than 10% of the patients had an observation time beyond 48 months. CI, confidence interval; CV, cardiovascular; EAC, event adjudication committee; HR, hazard ratio; MACE, major adverse cardiovascular event; PY, patient years. 1. Marso SP et al; N Engl J Med. 2016; 375: 311–322; 2. Marso SP; 52nd EASD Annual Meeting. 2016: Oral presentation S27.1. Available from: http://www.easdvirtualmeeting.org/contentsessions/2375 [Accessed March 2017].

LEADER: time to first incidence of each endpoint1,2

4,668

4,672

4,641

4,648

4,599

4,601

4,558

4,546

4,505

4,479

4,445

4,407

4,382

4,338

4,322

4,268

1,723

1,709

484

465

Patients at risk

Liraglutide

Placebo

0

5

10

15

20

0 6 18 24 30 36 42 48 54 12


Patients

with a

n e

vent

(%)


Incidence rate of liraglutide vs. placebo: 2.1 vs. 2.5 events/100 PY

HR: 0.85 (95% CI: 0.74; 0.97)

p=0.002

Liraglutide

Placebo

1) All-cause death*

4,668

4,672

4,612

4,612

4,550

4,540

4,483

4,464

4,414

4,372

4,337

4,288

4,258

4,187

4,185

4,107

1,662

1,647

467

442

0

5

10

15

20

0 6 18 24 30 36 42 48 54 12

Time from randomisation (months) Patients at risk

Liraglutide

Placebo


Liraglutide

Placebo

Patients

with a

n e

vent

(%)

3) Hospitalisation for heart failure* 4) Hospitalisation for heart failure or all-cause death**

0

5

10

15

20

0 6 18 24 30 36 42 48 54 12


Patients

with a

n e

vent

(%)

Liraglutide

Placebo


Patients at risk

Liraglutide

Placebo

4,668

4,672

4,641

4,648

4,599

4,601

4,558

4,546

4,505

4,479

4,445

4,407

4,382

4,338

4,322

4,268

1,723

1,709

484

465

HR: 0.87 (95% CI: 0.73; 1.05)

p=0.14

HR: 0.85 (95% CI: 0.74; 0.97)

p=0.002

0

5

10

15

20

25

0 6 18 24 30 36 42 48 54 12

4,668

4,672

4,515

4,506

4,356

4,336

4,221

4,157

4,063

4,002

3,914

3,857

3,793

3,697

3,682

3,581

1,452

1,410

395

366

Patients at risk

Liraglutide

Placebo


Patients

with a

n e

vent

(%)

HR: 0.88 (95% CI: 0.81; 0.96)

p=0.005

Liraglutide

Placebo

2) Expanded MACE* Incidence rate of liraglutide vs. placebo: 5.3 vs. 6.0 events/100 PY

LEADER: time to microvascular complications1,2

The cumulative incidences were estimated with the use of the Kaplan–Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months because less than 10% of the patients had an observation time beyond 54 months. *eGFR ≤45 ml/min/1.73 m2.2

ADA, American Diabetes Association; CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio.

1. Buse J; 76th ADA Annual Meeting. 2016: Oral presentation 3-CT-SY24. Available from: https://tracs.unc.edu/LEADER [Accessed March 2017]; 2. Marso SP et al; N Engl J Med. 2016; 375: 311–322.

Liraglutide is not indicated for cardiovascular risk reduction or renal risk reduction.

4,668

4,672

4,635

4,643

4,561

4,540

4,492

4,428

4,400

4,316

4,304

4,196

4,210

4,094

4,114

3,990

1,632

1,613

454

433

0 6 12 18 24 30 36 42 48 54

0

2

4

6

8

10


Patients at risk

Liraglutide


Placebo

Patients

with a

n e

vent

(%)

Liraglutide

Placebo

HR: 0.78 (95% CI: 0.67; 0.92)

p=0.003

Time to first renal event (macroalbuminuria, doubling of serum creatinine*, ESRD, renal death)

4,668

4,672

4,624

4,636

4,566

4,565

4,509

4,489

4,442

4,417

4,366

4,339

4,297

4,264

4,231

4,188

1,689

1,681

473

454

0 6 12 18 24 30 36 42 48 54

0

2

4

6

8

10


Patients at risk

Liraglutide

Placebo

Liraglutide

Placebo


HR: 1.15 (95% CI: 0.87; 1.52)

p=0.33

Patients

with a

n e

vent

(%)

Time to first eye event (photocoagulation or treatment with intravitreal agents, vitreous haemorrhage, or blindness

LEADER: summary of clinical and metabolic outcomes1,2

Data are estimated mean values from randomisation. ADA, American Diabetes Association; bpm, beats per minute; CI, confidence interval; CV, cardiovascular; dBP, diastolic blood pressure; EOT, end of treatment; ETD, estimated treatment difference; HbA1c, glycated haemoglobin; sBP, systolic blood pressure. 1. Marso SP et al; N Engl J Med. 2016; 375: 311–322; 2. Buse J; 76th ADA Annual Meeting. 2016: Oral presentation 3-CT-SY24. Available from: https://tracs.unc.edu/LEADER [Accessed March 2017].

HbA1c Weight

Heart rate Blood pressure

Liraglutide is not indicated for cardiovascular risk reduction; and doses of up to 1.8 mg are not indicated for weight management.

• LEADER demonstrated superiority for MACE (CV death, non-fatal MI and non-fatal stroke) with liraglutide treatment vs. placebo

– The incidence of the composite MACE endpoint was 3.4 events/100 patient-years with liraglutide compared with 3.9 events/100 patient-years with placebo

– HR corresponding to an estimated risk reduction for MACE of 13% was observed

• 608 patients (13.0%) in the liraglutide group vs. 694 patients (14.9%) in the placebo group: HR: 0.87 (95% CI: 0.78; 0.97); p<0.001 for non-inferiority; p=0.01 for superiority

– All three components of MACE contributed to the risk reduction

• Expanded MACE was also statistically significant in favour of liraglutide compared with placebo

– Incidence rate of liraglutide vs. placebo: 5.3 vs. 6.0 events/100 patient years (HR: 0.88 (95% CI: 0.81; 0.96), p=0.005

• This cohort comprised mostly those with established cardiovascular disease and included 46.2% of patients with moderate to severe renal impairment

• Liraglutide on top of standard of care reduces microvascular outcomes, particularly renal outcomes; this applies to a cohort at high CV and moderate renal risk

• No tolerability concerns around heart failure were identified

LEADER: summary

CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction.


Liraglutide is not indicated for cardiovascular or renal risk reduction or renal risk reduction.

0

5

10

15

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Sub

ject

s w

ith

an

eve

nt

(%)

Time since randomisation (weeks)

SUSTAIN-6: primary outcome Time to first occurrence of CV death, non-fatal MI, or non-fatal stroke

Kaplan-Meier plot for first event adjudication committee-confirmed CV death, non-fatal MI and non-fatal stroke using ‘in-trial’ data from subjects in the full analysis set. *Not prespecified. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction.


Patients at risk

Semaglutide 1,648 1,619 1,601 1,584 1,568 1,543 1,524

Placebo 1,649 1,616 1,586 1,567 1,534 1,508 1,479

Incidence rate of semaglutide vs. placebo: 3.24 vs. 4.44 events/100 patient-years

Semaglutide, 6.6%

Placebo, 8.9%

109

HR: 0.74 (95% CI: 0.58; 0.95)

p<0.001 for non-inferiority p=0.02 for superiority*

Marketing authorisation for semaglutide has been submitted and approval is currently awaited.

0

1

2

3

4

5

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Pa

tie

nts

wit

h a

n e

ven

t (%

)


SUSTAIN-6: time to each individual component of the primary composite endpoint

Kaplan–Meier plot for time from randomisation to first event adjudication committee-confirmed CV death, non-fatal MI or non-fatal stroke using ‘in-trial’ data from subject in the full analysis set. Hazard ratio is from a stratified proportional hazard model. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Marso SP et al; N Engl J Med. 2016; 375: 1834–1844.


Semaglutide, 2.7%

Placebo, 2.8%

109

1,648 1,634 1,627 1,617 1,607

1,649 1,637 1,623 1,617 1,600

1,589

1,584

1,579

1,566

Patients at risk

Semaglutide

Placebo

HR: 0.98 (95% CI: 0.65; 1.48)

p=0.92

Time to CV death

0

1

2

3

4

5

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Pa

tie

nts

wit

h a

n e

ven

t (%

)


Semaglutide, 2.9%

Placebo, 3.9%

109

Time to non-fatal MI Incidence rate of semaglutide vs. placebo: 1.40 vs. 1.92 events/100 patient-years

1,648 1,623 1,609 1,595 1,582

1,649 1,624 1,598 1,587 1,562

1,560

1,542

1,543

1,516

Patients at risk

Semaglutide

Placebo

0

1

2

3

4

5

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Pa

tien

ts w

ith

an

eve

nt

(%)


109

Time to non-fatal stroke

109


Semaglutide, 1.6%

Placebo, 2.7%

1,648 1,630 1,619 1,606 1,593

1,649 1,629 1,611 1,597 1,571

1,572

1,548

1,558

1,528

Patients at risk

Semaglutide

Placebo

HR: 0.74 (95% CI: 0.51; 1.08)

p=0.12

HR: 0.61 (95% CI: 0.38; 1.31)

p=0.04


SUSTAIN-6: time to microvascular complications

Kaplan-Meier plot for time from randomisation to first EAC-confirmed diabetic retinopathy complication or new or worsening nephropathy using ‘in-trial’ data from subjects in the full analysis set. Hazard ratio is from a proportional hazard model. CI, confidence interval; EAC, events adjudication committee; HR, hazard ratio; PY, patient-years.


0

2

4

6

8

0 8 16 24 32 40 48 56 64 72 80 88 96 104P

atie

nts

wit

h a

n e

ven

t (%

)

Weeks since randomisation

0

2

4

6

8

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Pat

ien

ts w

ith

an

eve

nt

(%)

Weeks since randomisation

Semaglutide, 3.8%

Placebo, 6.1%

1,525 1,648 1,630 1,605 1,580 1,563

1,649 1,629 1,570 1,545 1,518

1,541

1,498 1,471

Incidence rate of semaglutide vs. placebo: 1.86 vs. 3.06 events/100 PY

Patients at risk

Semaglutide

Placebo

HR: 0.64 (95% CI: 0.46; 0.88)

p=0.005

New or worsening nephropathy Diabetic retinopathy Incidence rate of semaglutide vs. placebo: 1.49 vs. 0.86 events/100 PY

HR: 1.76 (95% CI: 1.11; 2.78)

p=0.02 Semaglutide, 3.0%

Placebo, 1.8%

1,648 1,622 1,612 1,595 1,570

1,649 1,636 1,617 1,605 1,576

1,548

1,558

1,535

1,539

Patients at risk

Semaglutide

Placebo


SUSTAIN-6: summary of clinical and metabolic outcomes

Data are estimated mean values from randomisation. *Indicates significance (p value <0.0001). dBP, diastolic blood pressure; ETD, estimated treatment difference; HbA1c, glycated haemoglobin; sBP, systolic blood pressure.


HbA1c Weight

dBP

sBP


– Semaglutide reduced the risk for primary outcome by 26% vs. placebo (HR 0.74 [95% CI: 0.58; 0.95]; p<0.001 for non-inferiority; p=0.02 for superiority)1

– Semaglutide reduced the incidence rate for non-fatal stroke from 1.31 per 100 PY (placebo) to 0.80 per 100 PY (HR 0.61 [95% CI: 0.38; 0.99]; p=0.04 for superiority)

• Semaglutide reduced the incidence of nephropathy from 3.06 events per 100 PY (placebo) to 1.86 events per 100 PY1

• Semaglutide increased the incidence of retinopathy from 0.86 events per 100 PY (placebo) to 1.49 events per 100 PY1

• Semaglutide resulted in similar rates of hypoglycaemia and significant reductions compared to placebo in the following outcomes:

– HbA1c (p<0.0001) and body weight (p<0.0001) with both dosages1,2, and sBP (p<0.001) with 1.0 mg dose

• With the exception of complications of retinopathy, semaglutide had a tolerability profile similar to that of other GLP-1 receptor agonists3,4

SUSTAIN-6: summary

CI, confidence interval; HbA1c, glycated haemoglobin; HR, hazard ratio; LDL, low density lipoprotein; PY, patient-years; sBP, systolic blood pressure.

1. Marso SP et al; N Engl J Med. 2016; 375: 1834–1844; 2. Vilsbøll T; 52nd EASD Annual Meeting. 2016; Oral presentation [add nos.]. Available from: http://www.easdvirtualmeeting.org/contentsessions/2382 [Accessed June 2017]; 3. Diamant M et al; Lancet. 2010; 375: 2234–2243; 4. Marre M et al; Diabet Med. 2009; 26: 268–278.


ELIXA: primary outcome CV death, non-fatal MI, non-fatal stroke or hospitalisation for unstable angina

Kaplan–Meier plot for time from randomisation to first EAC-confirmed diabetic retinopathy complication using ‘in-trial’ data from subjects in the full analysis set. Hazard ratio is from a proportional hazard model. CI, confidence interval; CV, cardiovascular; EAC, events adjudication committee; HR, hazard ratio; MI, myocardial infarction.

Pfeffer MA et al. N Engl J Med. 2015; 373: 2247–2257.

Pat

ien

ts w

ith

an

eve

nt

(%)


3,034

3,034

2,785

2,759

1,558

1,566

484

476

0

0 12 24 36

5

10

15

20

Lixisenatide 13.4%

Placebo 13.2%

Lixisenatide is not licensed for cardiovascular risk reduction.

Incidence rate of lixisenatide vs. placebo: 6.4 vs. 6.3 events/100 patient-years

Patients at risk

Lixisenatide

Placebo

HR: 1.02 (95% CI: 0.89; 1.17)

p<0.001 for non-inferiority p=0.81 for superiority

ELIXA: hospitalisation for heart failure

CI, confidence interval; CV, cardiovascular; HR, hazard ratio; NS, non-significant.

Pfeffer MA et al; N Engl J Med. 2015; 373: 2247–2257.

0

0 12 24 36

5

10

15

20

Lixisenatide is not licensed for CV risk reduction

Pat

ien

ts w

ith

an

eve

nt

(%)


Incidence rate of lixisenatide vs. placebo: 1.9 vs. 1.8 events/100 patient-years

HR: 0.96 (95% CI: 0.75; 1.23)

p=NS

Lixisenatide Placebo

ELIXA: summary of clinical and metabolic outcomes

Data are estimated mean values from randomisation. bpm, beats per minute; CI, confidence interval; CV, cardiovascular; HbA1c, glycated haemoglobin; sBP, systolic blood pressure.


HbA1c Weight

Blood pressure Heart rate

Lixisenatide is not licensed for weight control, cardiovascular risk reduction or blood pressure control.

Mea

n G

lyca

ted

Hae

mo

glo

bin

(%

)

• In patients with type 2 diabetes and a recent acute coronary syndrome, treatment with lixisenatide resulted in rates of MACE, including heart failure and death from any cause, that were similar to those observed with placebo – Incidence rate of lixisenatide vs. placebo: 6.4 vs. 6.3 events/100 patient-

years

– HR 1.02 (95% CI: 0.89; 1.17); p<0.001 for non-inferiority; p=0.81 for superiority

ELIXA: summary

CI, confidence interval; HR, hazard ratio; MACE, major adverse cardiovascular event.


Lixisenatide is not licensed for cardiovascular risk reduction.

• An integrated meta-analysis of 12 completed randomised trials was performed to retrospectively examine the CV tolerability of exenatide BID

• Primary outcome was defined as MACE including terms reflective of CV mortality, stroke, MI, acute coronary syndrome and revascularisation procedures

• Secondary outcome included the terms in the primary outcome as well as terms for arrhythmia, heart failure and mechanical-related events

• This study found that exenatide BID does not increase CV risk measured by MACE (RR 0.7 [95% CI: 0.38; 1.31]) and secondary CV outcome (RR 0.69 [95% CI: 0.46; 1.03])

EXSCEL: cardiovascular effects of exenatide BID

BID, twice daily; CI, confidence interval; CV, cardiovascular; MACE, major adverse cardiovascular event; MI, myocardial infarction; RR, response rate.

Ratner R et al; Cardiovasc Diabet. 2011; 10: 22.

Marketing authorisation for exenatide has been submitted and approval is currently awaited.

LEADER1

• Liraglutide demonstrated superiority for MACE (CV-death, non-fatal MI and non-fatal stroke) vs. placebo

– Incidence rate of liraglutide vs. placebo: 3.4 vs. 3.9 events/100 patient-years

– HR (95% CI)=0.87 (0.78; 0.97); p<0.001 for non-inferiority and p=0.01 for superiority

SUSTAIN 62

• Semaglutide demonstrated superiority for MACE (CV-death, non-fatal MI and non-fatal stroke) vs. placebo

– Incidence rate of semaglutide vs. placebo: 3.24 vs. 4.44 events/100 patient-years


ELIXA3

• Lixisenatide demonstrated non-inferiority for MACE (CV-death, non-fatal MI and non-fatal stroke or hospitalisation for unstable angina) vs. placebo

– Incidence rate of lixisenatide vs. placebo: 6.4 vs. 6.3 events/100 patient-years


Overview of findings in CVOTs with GLP-1 RAs Time to primary endpoint

CI, confidence interval; CV, cardiovascular; CVOTs, cardiovascular outcome trials; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction. 1. Marso SP et al; N Engl J Med. 2016; 375: 311–322; 2. Marso SP et al; N Engl J Med. 2016; 375: 1834–1844; 3. Pfeffer MA et al. N Engl J Med 2015; 373: 2247–2257.

Liraglutide is not licensed for cardiovascular risk reduction. Semaglutide is not licensed for cardiovascular risk reduction. Lixisenatide is not licensed for cardiovascular risk reduction.

• To confirm the cardiovascular tolerability of insulin degludec compared to insulin glargine U100

DEVOTE: study design

*Defined as either cardiovascular or chronic kidney disease and aged ≥50 or ≥1 risk factors for cardiovascular disease and aged ≥60; †Confirmed by the Event Adjudication Committee; ‡ Severe defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon or take other corrective actions. d, days; IGlar U100, insulin glargine 100 units/ml; HbA1c, glycated haemoglobin; MACE, major adverse cardiovascular event; T2D, type 2 diabetes; U, units. Marso SP et al; N Engl J Med. 2017; doi:10.1056/NEJMoa1615692.

Insulin degludec once daily (blinded vial) + standard of care (n=3,818)

IGlar U100 once daily (blinded vial) + standard of care (n=3,819)

Randomisation End of treatment

(633 MACE accrued)

Follow-up period

30 d

Follow-up period

Interim analysis (150 MACE accrued)

Study design • Double-blind • Treat-to-target • Active controlled • Event-driven

N=7,637

Time to first occurrence of an adjudicated MACE consisting of CV death, non-fatal MI and non-fatal stroke

T2D, current treatment with ≥1 oral or injectable anti-diabetes agents, HbA1c ≥7.0% or <7.0% and basal insulin ≥20 U/day, high cardiovascular risk*

Primary endpoint

Key inclusion criteria

Insulin degludec is not licensed for cardiovascular risk reduction.

Rate of severe hypoglycaemic episodes†‡, incidence of severe hypoglycaemic episodes†‡ Key secondary endpoints

0

2

4

6

8

10

12

0 3 6 9 12 15 18 21 24 27 30

DEVOTE: primary endpoint

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

Full analysis set; Cox regression analysis accounting for treatment. Analysis includes events between randomisation date and follow-up date. Patients without an event are censored at the time of last contact (phone or visit). CI, confidence interval; CV, cardiovascular; EAC, Event Adjudication Committee; HR, hazard ratio; IGlar U100, insulin glargine 100 units/ml; MACE, major adverse cardiovascular events; MI, myocardial infarction; PYO, patient-years of observation. Adapted from: Marso SP et al; N Engl J Med. 2017; doi:10.1056/NEJMoa1615692.

HR: 0.91 (95% CI: 0.78; 1.06)

Non-inferiority confirmed p<0.001

Pat

ien

ts w

ith

an

eve

nt

(%)

3818 3765 3721 3699 3611 3563 3504 2851 1767 811 217

3819 3758 3703 3655 3595 3530 3472 2832 1742 811 205

Time to first EAC-confirmed event (months)

356 patients

325 patients

Rate: 4.71/100 PYO

Rate: 4.29/100 PYO

IGlar U100 Insulin degludec

Number of patients at risk

DEVOTE: rates of severe hypoglycaemia

Full analysis set; Mean number of confirmed severe hypoglycaemic episodes. The number of events is analysed using a negative binomial regression model using a log link and the logarithm of the observation time (100 years) as offset. CI, confidence interval; E, number of events; EAC, Event Adjudication Committee; IGlar U100, insulin glargine 100 units/ml; R, events per 100 patient-years of observation; PYO, patient-years of observation. Adapted from: Marso SP et al; N Engl J Med. 2017; doi:10.1056/NEJMoa1615692.

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30

Mea

n n

um

ber

of

even

ts/1

00

PYO


Insulin degludec (n=3818) IGlar U100 (n=3819)

E R E R

EAC-confirmed episodes 280 3.70 472 6.25

Rate ratio: 0.60 (95% CI: 0.48; 0.76)

p<0.001

IGlar U100 Insulin degludec

• Degludec was non-inferior to IGlar U100 with respect to the incidence of MACE

– Incidence rate of insulin degludec vs. IGlar U100: 4.29 vs. 4.71 events/100 patient-years

– HR: 0.91 (95% CI: 0.78; 1.06), p<0.001 for non-inferiority

• DEVOTE reported 752 adjudication-confirmed severe hypoglycaemic events in both arms combined in a blinded head-to-head trial

• Compared with IGlar U100, insulin degludec demonstrated a 40% lower rate of severe hypoglycaemia at similar levels of HbA1c

– Incidence rate of insulin degludec vs. IGlar U100: 3.70 vs. 6.25 events/100 patient-years

DEVOTE: summary

CI, confidence interval; EAC, Event Adjudication Committee; HbA1c, glycated haemoglobin; HR, hazard ratio; IGlar U100, insulin glargine 100 units/ml; MACE, major adverse cardiovascular events; PYO, patient-years of observation. Marso SP et al; N Engl J Med. 2017; doi:10.1056/NEJMoa1615692; Marso SP et al; ADA 2017; Symposium presentation 3-CT-SY22.

3.70 472 6.25

Treatment for T2D should aim to reduce CV risk

ADA, American Diabetes Association; AHA, American Heart Association; CV, cardiovascular; CVD, cardiovascular disease; EASD, European Association for the Study of Diabetes; ESC, European Society of Cardiology; T2D, type 2 diabetes. 1. Rydén L et al; Eur Heart J. 2013; 34: 3035–3087; 2. Fox CS et al; Circulation. 2015; 132: 691–718; 3. Piepoli MF et al; Eur Heart J. 2016; 37: 2315–2381.

ESC

/EA

SD1

AH

A/A

DA

2

The ESC have also published a 2016 guideline on CVD prevention including a section on diabetes3

Selected key messages

The multifactorial approach is very important in patients with T2D

Intensive management of hyperglycaemia reduces the risk of microvascular complications and, to a lesser extent, the risk of CVD. However, targets should be relaxed in the elderly, frail, those with long-duration DM and those with existing CVD

In DM patients with existing CVD, the use of a SGLT2 inhibitor substantially lessened CVD and total mortality and HF hospitalisation without major adverse effects. SGLT2 inhibitors should be considered early in the course of DM management in such patients

The ESC have published a 2016 guideline on CVD prevention including a section on diabetes

CVD, cardiovascular disease; DM, diabetes mellitus; ESC, European Society of Cardiology; HF, heart failure; SGLT2, sodium-glucose co-transporter 2; T2D, type 2 diabetes. Piepoli MF et al; Eur Heart J. 2016; 37: 2315–2381.

ESC guidelines were published in 2016 LEADER and SUSTAIN-6 data have since been published as well

Mechanisms of action

Home

Inflammation Glucose uptake Ischemic injury LV function Heart rate

Inflammation Endothelial function Vasodilation Plaque stability Blood flow Smooth muscle proliferation Platelet aggregation

CV effects of GLP-1

CV, cardiovascular; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor; LV, left ventricle.

Drucker DJ et al; Cell Metab. 2016; 24: 15–30.

GLP-1

GLP-1R

GLP-1R

Kidney

Heart

Platelets

Fat and other tissues

Brain

Blood vessels

Natriuresis

Diuresis

Blood pressure

Inflammation

Postprandial lipids

Glucose & hypoglycaemia

Cardioprotection

Body weight

GLP -1 Intestine

Alpha cell:

Glucagon secretion

Beta cell:

Insulin secretion & biosynthesis

Apoptosis

Coagulation

GLP-1 RAs have multifactorial effects

Liver

Brain Pancreas

Stomach

Cardiovascular risk2

Fatty acid metabolism3

Cardiac function3

Systolic blood

pressure3

Inflammation4

Endogenous glucose

production10

Hepatic insulin

sensitivity10

De novo lipogenesis10

Lipotoxicity10

Steatosis11

Beta-cell function1

Beta-cell apoptosis1

Insulin biosynthesis1

Glucose-dependent

insulin secretion1

Glucose-dependent

glucagon secretion1

Body weight5

Food intake5

Satiety7,8

Gastric emptying9

Heart

Portions of the content presented on this slide may originate from non-human studies, i.e., animal and in vitro studies. GLP-1 RA, glucagon-like peptide-1 receptor agonist.

Adapted from 1. Campbell JE, Drucker DJ; Cell Metab. 2013; 17: 819–837; 2. Pratley RE, Gilbert M; Rev Diabet Stud. 2008; 5: 73–94. A full reference list for this slide can be found in the slide notes.

GLP-1 RAs can provide a number of CV benefits

Evidence for these benefits originates from human and animal studies. CV, cardiovascular; GLP-1 RA, glucagon-like peptide-1 receptor agonist. Drucker DJ; Cell Metab. 2016; 24: 15–30; Ryan D, Acosta A; Obesity. 2015; 23: 1119–1129; Ussher JR, Drucker DJ; Circ Res. 2014; 114: 1788–1803.

GLP-1 RA

Improved cardiac function Myocardial glucose

uptake Cardiac function Cardioprotective

protein expression Left ventricular

function Ischaemic injury Small increase in heart rate

Prevention of atherogenesis Inflammation Endothelial

dysfunction Atherosclerotic plaque

progression Plaque stability CV benefits secondary to weight loss Improved lipid profiles

Effects on heart Effects on

blood vessels

Inflammation Endothelial function Vasodilation Plaque stability Blood flow Smooth muscle

proliferation Platelet aggregation

SGLT-2 inhibitors: mechanism of action

SGLT-2, sodium-glucose co-transporter 2. 1. Bhartia M et al; Rev Diabet Stud. 2011; 8: 348–354; 2. Lee YJ et al; Kidney Int Suppl. 2007; 106: S27–S35; 3. DeFronzo RA et al; Diabetes Obes Metab. 2012; 14: 5–14.

Reduced glucose reabsorption

Increased urinary excretion of excess

glucose

Proximal tubule

Glucose filtration

SGLT-2 inhibitor

SGLT-2

SGLT-2

Glucose

SGLT-2 inhibitor

• Inhibition of SGLT-2 promotes renal glucose excretion

• SGLT-2 is inhibited independently of blood glucose concentration

• Efficacy is independent of insulin secretion or insulin sensitivity

• However, efficacy is dependent on the amount of glucose filtered through the glomeruli, which depends upon:

– Plasma glucose levels

– Glomerular filtration rate

• Mudaliar et al have hypothesised that empagliflozin, an SGLT-2 inhibitor, improves myocardial fuel metabolism, myocardial contractility and cardiac efficiency:

• by shifting fuel utilisation away from lipids and glucose (which are less energy efficient) toward ketone bodies that produce ATP energy more efficiently than glucose or FFA and that act as a super fuel

Potential changes in myocardium fuel metabolism before and after SGLT-2i therapy

BHOB, beta-hydroxybutyrate; P/O Ratio, phosphate:oxygen ratio; SGLT-2i, sodium-glucose co-transporter-2 inhibitor; T2D, type 2 diabetes.

Adapted from: Mudaliar S et al; Diabetes Care. 2016; 39: 1115–1122.

T2D ↑ Fat oxidation

↓ Glucose oxidation ↓ P/O ratio

↓ Cardiac work efficiency

↓ Fat oxidation ↑ Glucose oxidation

↑↑ BHOB Ox ↑ P/O ratio

↑ Cardiac work efficiency

With SGLT2i Treatment

↑ Incidence/Progression

of Heart Failure

↓ Incidence/Progression

of Heart Failure

↑ Myocardial Contractility

↓ Myocardial Contractility

• The mechanism of action of SGLT-2 inhibitors also corrects a number of metabolic and haemodynamic abnormalities that are risk factors for CVD

– Urinary glucose loss produces negative caloric balance, resulting in a weight loss

– Natriuretic effects, combined with the more long-term reduction in body weight, contribute to decreases in systolic/diastolic blood pressure

• Because of the beneficial cardiometabolic/haemodynamic profile associated with SGLT-2 inhibitor therapy, one might expect that this class of drugs would lower CVD risk in T2D, independent of its glucose-lowering effect

SGLT-2 inhibitor rationale for cardiovascular risk reduction: haemodynamic effects

CVD, cardiovascular disease; SGLT-2 sodium-glucose co-transporter-2; T2D, type 2 diabetes.

Abdul-Ghani MA et al; Endocr Rev. 2011; 32: 515–531.

What are the possible mechanisms involved in SGLT-2i rationale for CV risk reduction?

Ketone bodies Fat and

glucose

Cardiac efficiency

Diuretic and Haemodynamic hypothesis:

Natriuresis

Negative caloric balance

Uricosuria

Inflammation Glucose toxicity

Plasma uric acid

Fuel Energetics

Hypothesis: Glycosuria

Plasma volume Activation of ACE2 – Ang1/7

Tubuloglomerular feedback

ACE2, angiotensin-converting enzyme-2; Ang1/7, angiotensin 1/7; HbA1c, glycated haemoglobin. Adapted from: Heerspink H et al; Circulation. 2016; 134: 752-772; Abdul-Ghani MA et al; Endocr Rev. 2011; 32: 515–531.

• Haemodynamic effects and clinical implications – Decreased intraglomerular pressure due to increased

afferent resistance in T1D-H patients – Decreased hyperfiltration

Pharmacological actions of SGLT2i’s and haemodynamic effects

SGLT2i, sodium-glucose co-transporter-2 inhibitor; T1D-H, type 1 diabetes-hyperfiltering. Škirtić M et al; Diabetologia. 2014; 57: 2599-2602.

Pharmacological

actions and filtration

Afferent

constriction

SGLT2 inhibition

pccs diabetes and the heart kdm ndm ifg igt ngt ausdiab = australian diabetes, obesity, and...

Documents