Traiter le risque cardiovasculaire dans le diabète de type 2 ......2018 ESC/ESH Hypertension...

Traiter le risque cardiovasculaire dans le diabète de type 2 -Au-delà du contrôle glycémique

2018 ESC/ESH Hypertension Guidelines

Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press

Presentation at the ESH Meeting, Barcelona June 9th, 2018

2018 ESC/ESH Guidelines for the management of arterial hypertensionThe Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH)

Authors/Task Force Members: Bryan Williams* (ESC Chairperson), Giuseppe Mancia* (ESHChairperson), Ileana Desormais, Wilko Spiering, Enrico Agabiti Rosei, Michel Azizi, Michel Burnier,Denis L. Clement, Antonio Coca, Giovanni de Simone, Anna Dominiczak, Thomas Kahan, FelixMahfoud, Josep Redon, Luis Ruilope, Alberto Zanchetti †, Mary Kerins, Sverre E. Kjeldsen,Reinhold Kreutz, Stephane Laurent, Gregory Y. H. Lip, Richard Mcmanus, Krzysztof Narkiewicz,Frank Ruschitzka, Roland E. Schmieder, Evgeny Shlyakhto, Costas Tsioufis, Victor Aboyans.

Document Reviewers: Guy De Backer (ESC Review Coordinator), Anthony M. Heagerty (ESHReview Coordinator), Stefan Agewall, Murielle Bochud, Claudio Borghi, Pierre Boutouyrie, JanaBrguljan, Héctor Bueno, Enrico G. Caiani, Bo Carlberg, Neil Chapman, Renata Cífková, John G. F.Cleland, Jean-Philippe Collet, Ioan Mircea Coman, Peter W. de Leeuw, Victoria Delgado, PaulDendale, Hans-Christoph Diener, Maria Dorobantu, Robert Fagard, Csaba Farsang, Marc Ferrini,Ian M. Graham, Guido Grassi, Hermann Haller, FD Richard Hobbs, Bojan Jelakovic, CatrionaJennings, Hugo A. Katus, Abraham A. Kroon, Christophe Leclercq, Dragan Lovic, Empar Lurbe,Athanasios J. Manolis, Theresa A. McDonagh, Franz Messerli, Maria Lorenza Muiesan, UweNixdorff, Michael Hecht Olsen, Gianfranco Parati, Joep Perk, Massimo Francesco Piepoli, JorgePolonia, Piotr Ponikowski, Dimitrios J. Richter, Stefano Rimoldi, Marco Roffi, Naveed Sattar, PetarM. Seferovic, Iain A. Simpson, Miguel Sousa-Uva, Alice V. Stanton, Philippe van de Borne, PanosVardas, Massimo Volpe, Sven Wassmann, Stephan Windecker, Jose Luis Zamorano



Classification of office BP and definitions of hypertension grade

Category Systolic

(mmHg)

Diastolic (mmHg)

Optimal < 120 and < 80

Normal 120–129 and/or 80–84

High normal 130–139 and/or 85–89

Grade 1 hypertension 140–159 and/or 90–99

Grade 2 hypertension 160–179 and/or 100–109

Grade 3 hypertension ≥ 180 and/or ≥ 110

Isolated systolic hypertension ≥ 140 and < 90



Factors influencing CV risk in patients with hypertension - 1

Demographic characteristics and laboratory parameters

Sex (men > women)

Age

Smoking – current or past history

Total cholesterol and HDL-C

Uric acid

Diabetes

Overweight or obesity

Family history of premature CVD (men aged < 55 years and women aged < 65 years)

Family or parental history of early onset hypertension

Early onset menopause

Sedentary lifestyle

Psychosocial and socioeconomic factors

Heart rate (resting values > 80 beats per min)!!



Factors influencing CV risk in patients with hypertension - 2Asymptomatic HMOD

Arterial stiffening: Pulse pressure (in older people) ≥ 60 mmHg

Carotid–femoral PWV > 10 m/s

ECG LVH

Echocardiographic LVH

Microalbuminuria or elevated albumin–creatinine ratio

Moderate CKD with eGFR > 30–59 mL/min/1.73 m2 (BSA) or severe CKD eGFR < 30 mL/min/1.73

m2

Ankle−brachial index < 0.9

Advanced retinopathy: haemorrhages or exudates, papilloedema

Established CV or renal disease

Cerebrovascular disease: ischaemic stroke, cerebral haemorrhage, TIA

CAD: myocardial infarction, angina, myocardial revascularization

Presence of atheromatous plaque on imaging

Heart failure, including HFpEF

Peripheral artery disease

Atrial fibrillation!



10-year CV risk categories (SCORE system)

Very high risk

People with any of the following:Documented CVD, either clinical or unequivocal on imaging.•Clinical CVD includes; acute myocardial infarction, acute coronary syndrome, coronary or other arterial revascularization, stroke, TIA, aortic aneurysm, PAD.•Unequivocal documented CVD on imaging includes: significant plaque (i.e. ≥ 50% stenosis) on angiography or ultrasound. It does not include increase in carotid intima-media thickness.Diabetes mellitus with target organ damage, e.g. proteinuria or a with a major risk factor such as grade 3 hypertension or hypercholesterolaemia Severe CKD (eGFR < 30 mL/min/1.73 m2)A calculated 10-year SCORE of ≥ 10%

High risk

People with any of the following:Marked elevation of a single risk factor, particularly cholesterol > 8 mmol/L (> 310 mg/dL) e.g. familial hypercholesterolaemia, grade 3 hypertension (BP ≥ 180/110 mmHg)Most other people with diabetes mellitus (except some young people with type 1 diabetes mellitus and without major risk factors, that may be moderate risk)Hypertensive LVHModerate CKD eGFR 30–59 mL/min/1.73 m2)A calculated 10-year SCORE of 5–10%

Moderate risk

People with:A calculated 10-year SCORE of 1% to < 5%Grade 2 hypertensionMany middle-aged people belong to this category

Low riskPeople with:A calculated 10-year SCORE of < 1%



Risk modifiers increasing CV risk estimated by the SCORE system

Social deprivation – the origin of many causes of CVD

Obesity (measured by BMI) and central obesity (measured by waist circumference)

Physical inactivityPsychosocial stress, including vital exhaustion

Family history of premature CVD (occurring at age < 55 years in men and < 60 years in women)

Autoimmune and other inflammatory disordersMajor psychiatric disordersTreatment for infection with human immunodeficiency virus Atrial fibrillationLV hypertrophyCKDObstructive sleep apnoea syndrome

!

!

!!!!

!



Correction factors for the SCORE CV risk estimates in first-generation immigrants to Europe

Region of origin Multiplication factor

Southern Asia 1.4

Sub-Saharan Africa 1.3

Caribbean 1.3

Western Asia 1.2

Northern Africa 0.9

Eastern Asia 0.7

South America 0.7



Classification of hypertension stages according to BP levels, presence of CV risk factors, HMOD, or comorbidities

Hypertension disease staging

Other risk factors, HMOD, or disease

BP (mmHg) grading

High-normalSBP 130−139DBP 85−89

Grade 1SBP 140−159DBP 90−99

Grade 2SBP 160−179DBP 100−109

Grade 3SBP ≥ 180DBP ≥ 110

Stage 1(uncomplicated)

No other risk factors Low risk Low risk Moderate risk High risk

1 or 2 risk factors Low risk Moderate risk Moderate − high risk High risk

≥ 3 risk factors Low –moderate risk

Moderate − high risk High risk High risk

Stage 2(asymptomatic

disease)

HMOD, CKD grade 3, or diabetes mellitus without

organ damage

Moderate − high risk High risk High risk High – very high

risk

Stage 3(symptomatic

disease)

Symptomatic CVD, CKD grade ≥ 4, or diabetes

mellitus with organ damage

Very high risk Very high risk Very high risk Very high risk

NB: HTA de stade x ou de grade x ?...






BP (mmHg) grading



Grade 2SBP 160−179DBP 100−109








disease)


organ damage


risk

Stage 3(symptomatic

disease)









BP (mmHg) grading



Grade 2SBP 160−179DBP 100−109








disease)


organ damage


risk

Stage 3(symptomatic

disease)






Screening and diagnosis of hypertension

!

!



Clinical indications for HBPM or ABPMConditions in which white-coat hypertension is more common, e.g.• Grade I hypertension on office BP measurement• Marked office BP elevation without HMODConditions in which masked hypertension is more common, e.g.• High-normal office BP• Normal office BP in individuals with HMOD or at high total CV riskPostural and post-prandial hypotension in untreated and treatedpatientsEvaluation of resistant hypertensionEvaluation of BP control, especially in treated higher-risk patientsExaggerated BP response to exerciseWhen there is considerable variability in the office BPEvaluating symptoms consistent with hypotension during treatmentSpecific indications for ABPM rather than HBPM:• Assessment of nocturnal BP values and dipping status (e.g.

suspicion of nocturnal hypertension, such as in sleep apnoea, CKD, diabetes, endocrine hypertension, or autonomic dysfunction)

!

!



BP measurement - 1Recommendations Class Level

Screening programmes for hypertension are recommended. All adults (18

years or older) should have their office BP measured and recorded in their

medical file and be aware of their BP.

I B

• Further BP recording is indicated, at least every 5 years if BP remains

optimal.

I C

• Further BP recording is indicated, at least every 3 years if BP remains

normal.

I C

• If BP remains high-normal, further BP recording, at least annually, is

recommended.

I C

• In older patients (> 50 years), more frequent screening of office BP

should be considered for each BP category because of the steeper rise in

SBP with ageing.

IIa C

It is recommended that office BP should be measured in both arms at least at

the first visit because a between-arm SBP difference of > 15 mmHg is

suggestive of atheromatous disease and is associated with an increased CV

risk.

I A

If a between-arm difference in BP is recorded, then it is recommended that

all subsequent BP readings use the arm with the higher BP reading.

I C

!

!



Key information to be collected in personal and family medical history - 2

History of possible secondary hypertension

Young onset of grade 2 or 3 hypertension (< 40 years), or sudden development of hypertension or rapidly worsening BP in older patients

History of renal/urinary tract disease

Recreational drug/substance abuse/concurrent therapies: corticosteroids, nasal vasoconstrictor, chemotherapy, yohimbine, liquorice

Repetitive episodes of sweating, headache, anxiety, palpitations, suggestive of pheochromocytoma

History of spontaneous or diuretic-provoked hypokalaemia, episodes of muscle weakness, and tetany (hyperaldosteronism)

Symptoms suggestive of thyroid disease or hyperparathyroidism

History of or current pregnancy and oral contraceptive use

History of sleep apnoea

Hypertension treatment

Current/past antihypertensive medication including effectiveness and intolerance to previous medications

Adherence to therapy!



Sensitivity to detect treatment-induced changes, reproducibility and operator independence, time to changes,

and prognostic value of changes provided by markers of HMOD

Marker of HMODSensitivity to

changes

Reproducibility and operator independence

Time to changesPrognostic value of the change

LVH by ECG Low HighModerate

(> 6 months)Yes

LVH by echocardiogram

Moderate Moderate Moderate(> 6 months)

Yes

LVH by CMR High HighModerate

(> 6 months)No data

eGFR Moderate High Very slow(years)

Yes

Urinary albumin excretion

High ModerateFast

(weeks to months)

Moderate

Carotid IMT Very low LowSlow

(> 12 months)No

PWV High LowFast

(weeks to months)

Limited data

Ankle−brachial index

Low ModerateSlow

(> 12 months)Moderate

!

!



Initiation of BP-lowering treatment (lifestyle changes and medication) at different initial office BP levels

Grade 3 hypertension

BP ≥ 180/ 110

High normal BP

BP 130-139 / 85-89


BP 140-159 / 90-99


BP 160-179 / 100-109

Lifestyle advice Lifestyle advice Lifestyle advice Lifestyle advice

Consider drug treatment in very high risk patients

with CVD, especially CAD

Immediate drug treatment in high or very high risk

patients with CVD, renal disease or

HMOD

Immediate drug treatment in all

patients

Immediate drug treatment in all

patients

Drug treatment in low-moderate risk patients without

CVD, renal disease or HMOD

after 3-6 months of lifestyle

intervention if BP not controlled

Aim for BP control within 3 months

Aim for BP control within 3 months! !



Core drug-treatment strategy for uncomplicated hypertension

The core algorithm is also appropriate for most patients with HMOD, cerebrovascular disease, diabetes, or PAD

!

!

!



Drug-treatment strategies

Core drug-treatment strategy for uncomplicated hypertension

Hypertension and CAD Hypertension and CKD

Hypertension and HRrEF Hypertension and AF



Office BP treatment target range

Age group

Office SBP treatment target ranges (mmHg) Diastolic treatment

target range

(mmHg)Hypertension + Diabetes + CKD + CAD + Stroke/TIA

18−65 years

Target to 130

or lower if

tolerated

Not < 120

Target to 130

or lower if

tolerated

Not < 120

Target to

< 140 to 130

if tolerated

Target to 130

or lower if

tolerated

Not < 120

Target to 130

or lower if

tolerated

Not < 120

< 80 to 70

65−79 yearsTarget to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

< 80 to 70

≥ 80 yearsTarget to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

< 80 to 70

Diastolic treatment target range(mmHg)

< 80 to 70 < 80 to 70 < 80 to 70 < 80 to 70 < 80 to 70

!



Office BP treatment target range

Age group

Office SBP treatment target ranges (mmHg) Diastolic treatment

target range

(mmHg)Hypertension + Diabetes + CKD + CAD + Stroke/TIA

18−65 years

Target to 130

or lower if

tolerated

Not < 120

Target to 130

or lower if

tolerated

Not < 120

Target to

< 140 to 130

if tolerated

Target to 130

or lower if

tolerted

Not < 120

Target to 130

or lower if

tolerated

Not < 120

< 80 to 70

65−79 yearsTarget to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

< 80 to 70

≥ 80 yearsTarget to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

Target to

< 140 to 130

if tolerated

< 80 to 70

Diastolic treatment target range(mmHg)

< 80 to 70 < 80 to 70 < 80 to 70 < 80 to 70 < 80 to 70

<65 ans et IRC: +/-125 / 75 mmHgsinon +/-135 / 75 mmHg


Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in pressMERCI POUR VOTRE ATTENTION !

Traiter le risque cardiovasculaire dans le diabète

de type 2 –Au-delà du contrôle glycémique

Conflit d’intérêt : interactions rémunérées avec l’industrie pharmaceutique dans le domaine de la prévention des affections cardiovasculaires (diabète, lipides, HTA, agrégation/thrombose)

In high-income countries, up to 91% of adults with diabetes have type 2 diabetes4

CVD is the leading cause of death among people with diabetes

*Information on diabetes type (i.e. type 1 or 2) was generally not available; however, the age of the participants suggests that the large majority with diabetes would have type 2. CI, confidence interval; CV, cardiovascular; CVD, CV disease; T2D, type 2 diabetes1. Seshasai SR et al. N Engl J Med 2011;364:829–841; 2. Rawshani A et al. N Engl J Med 2017;376:1407–1418; 3. Centers for Disease Control and Prevention. National Diabetes Fact Sheet 2011. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf; 4. International Diabetes Federation. IDF Diabetes Atlas, 8th edn. Brussels, Belgium: International Diabetes Federation, 2017. Available at: http://www.diabetesatlas.org

0

7

6

5

4

3

2

1

0

40 50 60 70 80 90

Age (years)

Yea

rs o

f lif

e lo

st

Men

7

6

5

4

3

2

1

0

40 50 60 70 80 900

Age (years)

Women

Non-vascular deaths

Vascular deaths

Years of life lost in people with diabetes*

compared with peers without diabetes1

0

50

100

150

200

250

1998-1

999

2000-2

001

2002-2

003

2003-2

004

2004-2

005

2006-2

007

2008-2

009

2010-2

011

2012-2

013

Patients with T2D

Matched controls

Sta

nd

ard

ised

in

cid

ence

rat

e(p

er 1

0,0

00

per

son

yea

rs)

Death from cardiovascular disease2

Heart disease is the cause of death in more than two-thirds of people

with diabetes aged 65 years or older3

The approach to reducecardiovascular risk in T2D is

multifactorial and individualized1-3

ACE-I, angiotensin-converting enzyme Inhibitors; ARB, angiotensin receptor blockers; T2D, type 2 diabetesAdpated from: 1. Rydén L, et al. Eur Heart J 2013;34:3035–87; 2. Fox CS, et al. Diabetes Care 2015;38:1777–803; 3. Piepoli MF, et al. Eur Heart J 2016;37:2315–81.

Lifestyle modification (weight control and physical

activity)Glycaemic

control

Blood pressure reduction

(ACE-I or ARB)

Dyslipidaemia control

(statin treatment)

Platelet inhibition (aspirine/other

anti-thrombotics)

Optimal cardiovascular risk reduction

GLP-1RA and SGLT-2i address a broad range of T2D-pathophysiologic defects

GLP-

1RA

SGLT-2i

↓ Blood Glucose

↓ Blood Pressure

↓ Body Weight

↓ Appetite↑ Glucose-dependent

insulin secretion

Slows gastric

emptying

↓ Systolic Blood

Pressure

↓ Vascular stiffness

↑ Urinary glucose

excretion

↓ Inflammation

Natriuresis

↑ Heart rate↓ Blood pressure↑ LV function↓ Infarct size

GLP-1RA = glucagon-like peptide-1 receptor agonist; SGLT-2i = sodium-glucose transporter-2 inhibitor

CVOTs showing a CV benefit on top of standard of care: GLP-1RAs

*Not pre-specified. CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; GLP-1RA, glucagon-like peptide 1 receptor agonist; HR, hazard ratio; MACE, major adverse cardiovascular events; T2D, type 2 diabetes1. 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

• Liraglutide superior to placebo for time to 3-point MACE in T2D with established CVD, chronic renal failure or aged ≥60 years with CV risk

LEADER1

(Victoza®)

Placebo

Liraglutide

0

5

10

15

20

0 6 12 18 24 30 36 42 48 54

Months

Patie

nts

with

eve

nt (

%)

HR: 0.87(95% CI: 0.78; 0.97)p<0.001 for non-inferiorityp=0.011 for superiority

• Semaglutide superiorto placebo for time to 3-point MACE in T2D with established CVD, chronic renal failure or aged ≥60 years with CV risk

SUSTAIN 62

(Ozempic®)

Semaglutide

Placebo

0

5

10

15

20

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

HR: 0.74 (95% CI: 0.58; 0.95)p<0.001 for non-inferiorityp=0.02 for superiority

Months

Patie

nts

with

eve

nt (

%)

2 4 6 8 10 12 14 16 18 20 22 24 26

GLP-

1 RA

GLP-1 RAs vary in molecular structure and size

CV, cardiovascular; GLP-1, glucagon-like peptide-1; GLP-1 RA, glucagon-like peptide-1 receptor agonist; IgG4 Fc, immunoglobulin-G4 fragment crystallisable.

Victoza®

(3.75 kDa, 97% homology)

C-16 fatty acid(palmitoyl)

HisAla Thr ThrSerPheGluGly AspVal

SerSerTyrLeuGluGlyAlaAla GlnLys

Glu

Glu

PheIle AlaTrpLeu GlyVal GlyArgArg

Ozempic®

(4.11 kDa, 94% homology)

C-18 fatty di-acid

COO

H

HisAib Thr ThrSerPheGluGly AspVal

SerSerTyrLeuGluGlyAlaAla Gln

Phe

LysGlu

IleAlaTrpLeu GlyVal GlyArgArg

Spacer

Lyxumia®

(4.86 kDa, ~50% homology)

HisGly Thr ThrSerPheGluGly Asp

Leu

Ser

LysGlnMetGluGluAlaVal GluArg

Phe

Leu

IleGluTrpLeu ProLys GlyGlyAsp SerSerGlyAlaProProProSer

HisGly Thr ThrSerPheGluGly AspLeu

Ser

LysGlnMetGluGluAlaVal GluArg

IleGluTrpLeu ProLys GlyGlyAsp SerSerGlyAlaProProProSerLysLys

LysLysLysLys

Phe

Leu

Byetta®/Bydureon®

(4.19 kDa, 53% homology)Trulicity®

(~63 kDa, 90% homology)

HisGly Thr ThrSerPheGluGly AspValSer

SerTyrLeuGluGluAlaAla GlnLys

PheGlu

IleAlaTrpLeu GlyVal GlyGlyLys

PheIleAlaTrpLeu GlyVal GlyGlyLysGlu

SerTyrLeuGluGluAlaAla GlnLysSer

HisGly Thr ThrSerPheGluGly AspValLinker peptide

Modified IgG4 Fc domain

Exendin-based GLP-1RAs

Human GLP-1 analogues

Small Large

Eperzan®*

HisGly Thr ThrSerPheGluGly AspValSerSerTyrLeuGluGly AlaAla

Gln

Lys

PheGluIleAlaTrpLeuGly ValGlyArg LysHisGlyThrThrSer

Phe GluGly

AspValSerSerTyrLeuGluGly AlaAlaGln Lys PheGlu IleAlaTrp

Leu

Asp

Val

GlyArg

Lys

ALBUMIN

Eperzan® was withdrawn from the worldwide market in July 2018

NEW since1 May 2019

May 2019 (Belgium)

• Dapagliflozin was superior to placebo for CV death or hospitalisation for HF in T2D with established or high-risk CVD

DECLARE-TIMI 583

0

5

10

15

20

0 6 12 18 24 30 36 42 48

Placebo

Dapagliflozin

Patie

nts

with

eve

nt (

%)

Months

HR: 0.8395% CI: 0.73; 0.95p=0.005 for superiority

CVOTs showing a CV benefit on top of standard of care: SGLT-2is

Dapagliflozin was not superior to placebo for time to 3-point MACE in T2D with established or high-risk CVD

DECLARE-TIMI 583

(Forxiga®)

0

5

10

15

20

0 6 12 18 24 30 36 42 48

Placebo

Dapagliflozin

Patie

nts

with

eve

nt (

%)

Months

HR: 0.9395% CI: 0.84; 1.03p=0.17 for superiorityp<0.001 for non-inferiority

CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiovascular events; SGLT-2i, sodium–glucose co-transporter-2 inhibitor; T2D, type 2 diabetes1. Zinman B et al. N Engl J Med 2015;373:2117–2128; 2. Neal B et al. N Engl J Med 2017;377:644–657; 3. Wiviott SD et al. N Engl J Med 2018; doi:10.1056/NEJMoa1812389 [Epub ahead of print]

Empagliflozin was superior to placebo for time to 3-point MACE in T2D with established CVD

EMPA-REG OUTCOME1

(Jardiance®)

Months

0 6 12 18 3024 4236 48

20

10

5

0

15

HR: 0.8695.02% CI: 0.74; 0.99p<0.001 for non-inferiorityp=0.04 for superiority

Patie

nts

with

eve

nt (

%) Placebo

Empagliflozin

Canagliflozin was superior to placebo for time to 3-point MACE in T2D with established CVD or ≥50 years with high-risk CVD

CANVAS2

(Invokana®)

Placebo

Canagliflozin

0 6 12 18 24 30 36 42 48 54 60 66 72 780

5

10

15

20

Months

Patie

nts

with

eve

nt (

%)

HR: 0.86 95% CI: 0.75; 0.97p<0.001 for non-inferiorityp=0.02 for superiority

Prevalence of CVD in the Scottish Care Information (SCI)-Diabetes registry

Use of anti-glycaemic drugs with CV benefit is limited

• In an analysis of the SCI-Diabetes registry, which included observational data from 248,000 patients with diabetes, use of GLP-1RAs and SGLT-2is was low, irrespective of patient history of CVD

CVD, cardiovascular disease; GLP-1RA, glucagon-like peptide 1 receptor agonist; SGLT-2i, sodium-glucose co-transporter 2 inhibitor; T2D, type 2 diabetesMcGurnaghan S et al. Diabet Med 2018; doi: 10.1111/dme.13825 [Epub ahead of print]

In patients with CVD:

2.4% were on a GLP-1RA

1.4% were on an SGLT-2i

In patients without CVD:

2.9% were on a GLP-1RA

2.2% were on an SGLT-2i

Evidence Hierarchy

Choosing glucose-lowering medication

†Be aware that SGLT-2is vary by region and individual agent with regard to indicated level of eGFR for initiation and continued use; ‡Both empagliflozin and canagliflozin have shown reduction in HF and reduction in CKD progression in CVOTs; §Degludec or U100 glargine have demonstrated CVD safety; ¶Low dose may be better tolerated, although less well studied for CVD effects; ||Choose later-generation SU with lower risk of hypoglycaemiaDavies MJ et al. Diabetologia 2018;61:2461–2498

In patients with established ASCVD

Liraglutide Semaglutide Exenatide ER

ASCVD predominates

If further intensification is required or patient is now unable to tolerate GLP-1RA and/or SGLT-2i, choose agents demonstrating CV safety:• Consider adding the other class (GLP-1RA or SGLT-2i) with

proven CVD benefit• DPP-4i if not on GLP-1RA• Basal insulin§

• TZD¶

• SU||

If HbA1c above target

GLP-1RA with proven CVD

benefit

SGLT-2i with proven CVD

benefit,if eGFR adequate†

EITHER/OR

Evidence Hierarchy

Empagliflozin Canagliflozin

Evidence modestly stronger for empagliflozin vs canagliflozin

Evidence of benefit strongest for liraglutide; favourable for semaglutide;less certain for exenatide

NB: Direct comparison of studies should be interpreted with caution due to differences in study design,

populations and methodology

Evidence Hierarchy


†Be aware that SGLT-2is vary by region and individual agent with regard to indicated level of eGFR for initiation and continued use; ‡Both empagliflozin and canagliflozin have shown reduction in HF and reduction in CKD progression in CVOTs; §Degludec or U100 glargine have demonstrated CVD safety; ¶Low dose may be better tolerated, although less well studied for CVD effects; ||Choose later-generation SU with lower risk of hypoglycaemiaDavies MJ et al. Diabetologia 2018;61:2461–2498

In patients with established ASCVD


ASCVD predominates

If further intensification is required or patient is now unable to tolerate GLP-1RA and/or SGLT-2i, choose agents demonstrating CV safety:• Consider adding the other class (GLP-1RA or SGLT-2i) with

proven CVD benefit• DPP-4i if not on GLP-1RA• Basal insulin§

• TZD¶

• SU||


GLP-1RA with proven CVD

benefit

SGLT-2i with proven CVD

benefit,if eGFR adequate†

EITHER/OR

Evidence Hierarchy


Evidence modestly stronger for empagliflozin vs canagliflozin

Evidence of benefit strongest for liraglutide; favourable for semaglutide;less certain for exenatide

?

Reduction in cardiovascular death of 51% (HR 0.49, p=0.03) Reduction in all-cause mortality of 49% (HR 0.51, p=0.008)

But: non-fatal myocardial infarction (HR 1.18, non-significant)

and non-fatal stroke (HR 0.74, non-significant)


*†Be aware that SGLT-2is vary by region and individual agent with regard to indicated level of eGFR for initiation and continued use; ‡Both empagliflozin and canagliflozin have shown reduction in HF and reduction in CKD progression in CVOTs; §Degludec or U100 glargine have demonstrated CVD safety; ||Choose later-generation SU with lower risk of hypoglycaemia; #Caution with GLP-1RA in ESRDDavies MJ et al. Diabetologia 2018;61:2461–2498

In patients with established HF or CKD

HF OR CKD predominates

• Avoid TZD in the setting of HF

Choose agents demonstrating CV safety:• Consider adding the other class with proven CVD benefit• DPP-4i (not saxagliptin) in the setting of HF (if not on GLP-1RA)• Basal insulin§

• SU||


SGLT-2i with evidence of reducing HF and/or CKD progression in CVOT if eGFR adequate‡

If SGLT-2i not tolerated or contraindicated or if eGFR less than adequate†, add GLP-1RA with proven CV benefit*#

OR

PREFERABLY

Evidence Hierarchy


Evidence Hierarchy


• SGLT-2is preferred over GLP-1RAs as significant, consistent reductions in hospitalisation for HF and CKD progression have been seen in SGLT-2i trials

NB: Direct comparison of studies should be interpreted with caution due to differences in study design,

populations and methodology

Managing Patients with Established ASCVD and T2D

† The available evidence for cardiovascular event reduction in patients with T2D and clinical ASCVD is derived from trials where most participants were on metformin at baseline. * Until further data from ongoing clinical trials become available, patients at high risk for HF (and possibly those with established HF) may derive more benefit from an SGLT2i with demonstrated CV benefit.Das SR et al. J Am Coll Cardiol 2018. https://doi.org/10.1016/j.jacc.2018.09.020

Yes YesPatient ≥ 18 years AND

T2D and established clinical ASCVD? Do not start SGLT2i or GLP-1RA

Start GLP-1RAStart SGLT2i*

ESRD or ongoing pregnancy orcurrently breastfeeding?

Insufficient evidence to recommend SGLT2i or GLP-1RA for ASCVD risk

reductionConsider starting a SGLT2i or GLP-1RA†

Initiate discussion incorporating patient and clinician preferences and priorities

Patient does not wish to start SGLT2i or GLP-1RA GLP-1RA is selected SGLT2i is selected

Continue to monitor response to therapy

Continue to monitor response to therapy

NoNo

Managing Patients with Established ASCVD and T2D

* eGFR <45 ml/min/1.73 m2 is currently a caution due to a decrease in glycemic efficacy (not due to safety), but SGLT2i are currently being investigated for nephroprotection in these patientsDas SR et al. J Am Coll Cardiol 2018. https://doi.org/10.1016/j.jacc.2018.09.020

Consider Using a GLP-1RA First When Patient and Clinician Priorities Include:

Reducing MACE and CV death

Preventing heart failure hospitalization

Reducing blood pressure

Orally administered therapies

Reducing MACE and CV death

Weight loss

Once weekly (subcutaneous) dosing

Therapy when eGFR consistently <45 ml/min/1.73 m2*

Consider Using an SGLT2i First When Patient and Clinician Priorities Include:

-1.5-1.6

-1.3

-1.6

-0.5

-1.5

-0.9

-1.5

-1.1

-1.8

-1.4

-1.2

-1.6

-0.8

-1.4

-1.8

-0.1

-2.0

-1.5

-1.0

-0.5

0.0

Cha

nge

from

bas

elin

e in

HbA

1c(%

)

Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo Sitagliptin 100 mgExenatide ER 2.0 mg Dulaglutide 0.75 mg Dulaglutide 1.5 mg IGlar

–1.6

<–0.1

*

Semaglutide (Ozempic®) : Superior in HbA1c reduction vs. placebo, sitagliptin, exenatide,

dulaglutide, IGlar.SUSTAIN 1–5 and 7

*p<0.0001 vs comparator. Exenatide ER, exenatide extended release; IGlar, insulin glargine; MET, metformin; N/A, not applicable; OAD, oral antidiabetic drug; SU, sulphonylurea; TZD, thiazolidinedione; w, weeks. 1. Sorli C et al. Lancet Diabetes Endocrinol 2017;5:251–60; 2. Ahrén B et al. Lancet Diabetes Endocrinol 2017;5:341–54; 3. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 4. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 5. Aroda VR et al. Lancet Diabetes Endocrinol 2017;5:355–66; 6; Rodbard HW et al. J Clin Endocrinol Metab 2018;103:2291–301.

**

*

** *

*

*

*

*

MONOTHERAPY ADD-ON TO OAD VS/ADD-ON TO BASAL

INSULIN

Comparator: Placebo1 Januvia®2 Bydureon®3 Trulicity®4 Lantus®5 Placebo6

Background: N/A MET±TZD 1–2 OADs(MET/TZD/SU) MET MET±SU Add-on to basal

insulin±METTreatment duration

(w): 30 56 56 40 30 30

Baseline HbA1c(%): 8.1 8.1 8.3 8.2 8.2 8.4

SUSTAIN 1 SUSTAIN 2 SUSTAIN 3 SUSTAIN 7 SUSTAIN 4 SUSTAIN 5

<-0,1% -0,1%

-3.7

-4.5

-1.0

-4.3

-6.1

-1.9

-5.6

-1.9

-4.6

-2.3

-6.5

-3.0-3.5

-5.2

1.2

-3.7

-6.4

-1.4

-8.0

-6.0

-4.0

-2.0

0.0

2.0

Cha

nge

from

bas

elin

e in

BW

(kg

)

Semaglutide 0.5 mg Semaglutide 1.0 mg Placebo Sitagliptin 100 mgExenatide ER 2.0 mg Dulaglutide 0.75 mg Dulaglutide 1.5 mg IGlar

*

Semaglutide (Ozempic®): Superior in body weight reduction vs. placebo, sitagliptin, exenatide,

dulaglutide, IGlar.SUSTAIN 1–5 and 7

*p<0.0001 vs comparator. BW, body weight; exenatide ER, exenatide extended release; IGlar, insulin glargine; MET, metformin; N/A, not applicable; OAD, oral antidiabetic drug; SU, sulphonylurea; TZD, thiazolidinedione; w, weeks. 1. Sorli C et al. Lancet Diabetes Endocrinol 2017;5:251–60; 2. Ahrén B et al. Lancet Diabetes Endocrinol 2017;5:341–54; 3. Ahmann AJ et al. Diabetes Care 2018;41:258–66; 4. Pratley RE et al. Lancet Diabetes Endocrinol 2018;6:275–86; 5. Aroda VR et al. Lancet Diabetes Endocrinol 2017;5:355–66; 6; Rodbard HW et al. J Clin Endocrinol Metab 2018;103:2291–301.

*

* *

**

*

*

*

*

*

MONOTHERAPY ADD-ON TO OAD VS/ADD-ON TO BASAL

INSULIN

Comparator: Placebo1 Januvia®2 Bydureon®3 Trulicity®4 Lantus®5 Placebo6

Background: N/A MET±TZD 1–2 OADs(MET/TZD/SU) MET MET±SU Add-on to basal

insulin±METTreatmentduration (w): 30 56 56 40 30 30

Baseline BW(kg): 91.9 89.9 95.8 95.2 93.5 91.7

SUSTAIN 1 SUSTAIN 2 SUSTAIN 3 SUSTAIN 7 SUSTAIN 4 SUSTAIN 5

*EOT may be any time from month 42 onwardsCVOT, cardiovascular outcomes trial; EOT, end of trial; SBP, systolic blood pressure; GLP-1RA, glucagon-like peptide-1 receptor agonist1. Marso et al. N Engl J Med 2016;375:1834–44

Change in systolic blood pressure with Semaglutide (Ozempic®) CVOT

SUSTAIN 6

126

127

128

129

130

131

132

133

134

135

136

137

138

92 10416 44 680 30 56 80

0.0

24

Time from randomisation (weeks)

SBP

(mm

Hg)

Placebo 0.5 mgPlacebo 1.0 mgSemaglutide 0.5 mgSemaglutide 1.0 mg

SUSTAIN 61

Semaglutide (Ozempic®): for which patients?

•Insufficently controlled (HbA1c >7.5%)•AND

•Body mass index (BMI) ≥30kg/m²•AND

•Treated for at least 3 months with at least metformin

En Belgique, à partir du 1er juillet (tous les GLP-1RA)

Semaglutide (Ozempic®) posology:

Ozempic® Summary of Product Characteristics November 2018

MERCI POUR VOTRE ATTENTION !

Traiter le risque cardiovasculaire dans le

diabète de type 2 –Au-delà du contrôle

glycémique

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Traiter le risque cardiovasculaire dans le diabète de type 2 ......2018 ESC/ESH Hypertension...

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