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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
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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)!!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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%
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
!
!
!!!!
!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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 ?...
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
Screening and diagnosis of hypertension
!
!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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)
!
!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
!
!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
!
!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
Grade 1 hypertension
BP 140-159 / 90-99
Grade 2 hypertension
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! !
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
Core drug-treatment strategy for uncomplicated hypertension
The core algorithm is also appropriate for most patients with HMOD, cerebrovascular disease, diabetes, or PAD
!
!
!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
Drug-treatment strategies
Core drug-treatment strategy for uncomplicated hypertension
Hypertension and CAD Hypertension and CKD
Hypertension and HRrEF Hypertension and AF
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
!
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018 and Eur Heart J 2018, in press
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
2018 ESC/ESH Hypertension Guidelines
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
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
?
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)
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; ||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||
If HbA1c above target
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
Empagliflozin Canagliflozin
Evidence Hierarchy
Liraglutide Semaglutide Exenatide ER
• 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