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Ré#nopathiediabé#que:29%chezlesdiabé#ques
de≥40ans
Principalecausedecécité
Principalecaused’amputa#onnontrauma#quedesmembresinférieurs
Néphropathiediabé#que:44%del’ensembledesnouveauxcas
d’insuffisancerénaleen2008
Principalecaused’insuffisancerénaleterminale:
±10%décèdentd’insuffisancerénale
Accidentvasculairecérébral
Affections cardiovasculaires risque 2x plus élevé
Augmenta#ondelamortalitécardiovasculaireetdesAVC
3.Na#onalDiabetesInforma#onClearinghouse.DiabetesSta#s#cs–Complica#onsofDiabetes.(website)hVp://www.niddk.nih.gov/health/diabetes/pubs/dmstats/dmstats.htm
Complications chroniques du diabète
Neuropathiediabé#que:60%del’ensembledesamputa#ons
nontrauma#quesdemembreschezl’adulte
CV disease is the single leading cause of mortality in type 2 diabetes
1. Morrish NJ et al. Diabetologia 2001;44:S14–21; 2. Hansen M, et al. Diabetologia 2012;55:294–302.
Of all CVD deaths in T2DM:2 • Ischaemic heart
disease=53.6% • Cerebrovascular
disease=26.2% • Other CVD=20.2%
Multinational WHO data on causes of mortality in T2DM1
Other causes
21%
Cancer
14%
Renal disease
11%
Diabetes
3%
CV disease 52%
Heart failure
Diabetes, heart failure and mortality risk Patients with Heart failure
DM patients + Heart failure i.e. 10-fold more than diabetics without HF
DIE WITHIN 3 YEARS OF DIAGNOSIS
DM patients
DIE WITHIN 3 YEARS OF DIAGNOSIS
1.Voors A – Heart 2011;97:774-780 2. Fitchett et al – European journal of heart failure 2017, 19;43-53
CVD is the leading cause of death in people with T2D
1. Seshasai et al. N Engl J Med 2011;364:829-41; 2. Centers for Disease Control and Prevention National Diabetes Fact Sheet 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf; 3. International Diabetes Federation. IDF Diabetes Atlas, 7th edition. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org
*Information on diabetes type (i.e., type 1 or 2) was generally not available, though the age of the participants suggests that the large majority with diabetes would have type 2. In high income countries, up to 91% of adults with diabetes have type 23 CVD, cardiovascular disease; CI, confidence interval; T2D, type 2 diabetes.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Soulage Soulages
Soulages
Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials
Study Microvasc CVD Mortality
UKPDS ! ! "# ! "# !
DCCT/EDIC* ! ! "# ! "# "#
ACCORD ! "# $ADVANCE ! "# "#
VADT ! "#* In diabetes type 1
Kendall DM, Bergenstal RM. © International Diabetes Center 2009 -UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854.
Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977.
Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545.
Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum:
Moritz T. N Engl J Med 2009;361:1024)
Effets de l’ excellence glycémique sur le développement des complications chroniques
Défis du traitement du diabète de type 2
- Prévenir les complications micro et macrovasculaires
Le contrôle strict de la glycémie a un effet limité sur les complications macrovasculaires
Turnbull FM et al. Diabetologia 2009;52:2288
La méta-analyse basée sur 27 049 patients et 2 370 événements cardiovasculaires
Rapport de risque (IC à 95 %)
ACCORD 257 (1.41) 203 (1.14) -1.01
ADVANCE 498 (1.86) 533 (1.99) -0.72
UKPDS 123 (0.13) 53 (0.25) -0.66
VADT 102 (2.22) 95 (2.06) -1.16
Total 980 884 -0.88
ACCORD 137 (0.79) 94 (0.56) -1.01
ADVANCE 253 (0.95) 289 (1.08) -0.72
UKPDS 71 (0.53) 29 (0.52) -0.66
VADT 38 (0.83) 29 (0.63) -1.16
Total 497 441 -0.88
Mortalité
Décès cardiovasculaires
Études
Nombre d'événements (taux d'événements annuels, %)
Traitement intensif
Traitement moins intensif
∆HbA1c (%)
Avantage du traitement intensif
Avantage du traitement moins intensif
HR total (IC 95 %)
1.04 (0.90, 1.20)
1.10 (0.84, 1.42)
0.5 2.0 1.0
BE/DIA/00069a 05/2017
BuyBuysschaert et al, Current Diabetes Reviews, 2016B
IRC
Buysschaert et al, Current Diabetes Reviews, 2016
Pathogenic pathways
Updated ADA guidelines 2018
Key elements for type 2 diabetes
Patient and disease factors used to determine optimal A1C targets
American Diabetes Association Diabetes Care. 2018 ©2018 by American Diabetes Association
Gæde P. et al. New Eng J Med 2008, 358 (6): 580-591.
STENO-2 FOLLOW-UP: résultats après 13.3 années Après 23 ans, progression vers macroalb/ ESRD/ ESRD et décès HR:0.48 /0.36/0.53 Oellgaard et al , Kidney Int, 2017
Antihyperglycemic therapy in type 2 diabetes: general recommendations
American Diabetes Association Diabetes Care 2018
En 2018, le « cardiovasculaire » devient un paramètre que le clinicien peut (doit) intégrer dans son choix thérapeutique sur base d’études validées.
1.
Kaplan-Meier Curves for Four Prespecified Aggregate Clinical Outcomes
Holman RR et al. N Engl J Med 2008;359:1577-1589
Holman et al, 2008
10-year UKPDS post-trial of intensive control (1998-2007)
any diabetes- related endpoint : 21 % p=0.01 myocardial infarction : 33% p=0.005 death any cause: 27% p=0.002
The cv risk reduction - metf vs conventional treatment - persisted 10 years later…
Primary Outcome.
Kernan WN et al. N Engl J Med 2016;374:1321-1331
Kernan et al, 2016
In non diabetic subjects with insulin resistance
9.0%
11.8%
Fatal or not fatal stroke or myocardial infarction
Herge, le Lotus Bleu
et les agonistes du GLP-1 ?
Evolution of anthropometric parameters at 6 and 12 months
Baseline 6 months
12 months ∆ from 0 to 12 months
Weight (kg) 95±19 93±19 92±19 -3,0±5,4
BMI (kg/m²) 33,9±6,2 33,2±6,5 32,8±6,3 -0,89±2,0
Waist Circumference (cm)
112±14 110±14 110±13 -3,4±5,6
Blood Pressure (mmHg)
Systolic 138±18 135±16 136±16 -2,6±19,5
Diastolic 81±10 79±8 79±9 -1,6±10,4 Data are mean ± SD
***
***
***
*
NS
*** p<0.001 * p=0.059 NS= Not Significant
Buysschaert et al, 2015
ETUDE ROOTS
HbA1c -1.5%
LEADER: Study design
CV: cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; HbA1c: glycated hemoglobin; MEN-2: multiple endocrine neoplasia type 2; MTC: medullary thyroid cancer; OAD: oral antidiabetic drug; OD: once daily; T2DM: type 2 diabetes mellitus.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
GLP-1 agonists : association with CV protection ?
Primary objective: MACE
3.8 ans
LEADER: Study design
CV: cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; HbA1c: glycated hemoglobin; MEN-2: multiple endocrine neoplasia type 2; MTC: medullary thyroid cancer; OAD: oral antidiabetic drug; OD: once daily; T2DM: type 2 diabetes mellitus.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
GLP-1 agonists : association with CV protection
Primary objective: MACE
3.8 ans
Primary outcome CV death, non-fatal myocardial infarction 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-hazards 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
Marso SP et al. N Engl J Med 2016;375:311–322
-13%
All cause death -15%
CV death
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.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
-22%
Recurrent CV event analysis Total CV death, non-fatal myocardial infarction or non-fatal stroke
Post-hoc analysis. Analysis based on an Andersen–Gill intensity model with treatment group as an explanatory variable and number of previous events as a time-dependent covariate CI: confidence interval; EAC: event adjudication committee
Presented at the American Diabetes Association 77th Scientific Sessions, Session 1-AC-SY13. June 11 2017, San Diego, CA, USA
Glucagon-like peptide-1 receptor agonists
CI: confidence interval; CV: cardiovascular; HR: hazard ratio; MI: myocardial infarction. Pfeffer MA et al. N Engl J Med 2015;373:2247–2257.
ELIXA Time to first occurrence of CV death, non-fatal MI, non-fatal stroke or hospitalization for unstable angina
LEADER Time to first occurrence of CV death, non-fatal MI or non-fatal stroke
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
lixisenatide liraglutide
Trial Outcomes.
Holman RR et al. N Engl J Med 2017;377:1228-1239
Holman et al, 2017
EXCEL
et les gliflozines ?
glycosurie +
Buysschaert, Louvain Méd, 2015
Zinman B. et al., N Engl J Med, 2015: 373(22):2117-28 BE/EMP/00085 a 07/2016
EMPA-REG OUTCOME®
Randomised, double-blind, placebo-controlled CV outcomes trial Objective
To examine the long-term effects of empagliflozin versus placebo, in addition to standard of care, on CV morbidity and mortality in patients with type 2 diabetes and high risk of CV events
Objectif primaire: 3 MACE (décès CV, infarctus ou AVC non fatal) Objectifs secondaires: 4 MACE, événements CV individuellement, insuffisance cardiaque, microangiopathie
Inhibiteurs du SGLT2
- EMPA-REG OUTCOME
Fonction cumulative-incidence. MACE, Major Adverse Cardiovascular Event (évènement cardiovasculaire indésirable majeur) ; HR, hazard ratio. *Des analyses bilatérales sont réalisées sur la supériorité (pertinence statistique si p ≤0,0498)
Zinman B. et al., N Engl J Med, 2015: 373(22):2117-28
- 14% Réduction du risque
3P-MACE (décès CV, IM non fatal, AVC non fatal)
BE/DIA/00069a 05/2017
Inhibiteurs du SGLT2
- EMPA-REG OUTCOME
Fonction cumulative-incidence. HR, hazard ratio
- 38% Réduction du risque
Zinman B. et al., N Engl J Med, 2015: 373(22):2117-28
Décès cardiovasculaires
BE/DIA/00069a 05/2017
Inhibiteurs du SGLT2
- EMPA-REG OUTCOME
Fonction cumulative-incidence. HR, hazard ratio
Zinman B. et al., N Engl J Med, 2015: 373(22):2117-28
Hospitalisation pour insuffisance cardiaque
- 35% Réduction du risque
BE/DIA/00069a 05/2017
Décès cardiovasculaires et pathologies cardiaques à l’inclusion
Fitchett et al, 2018
EMPA-REG & CANVAS Program: Primary MACE Outcome CV Death, Nonfatal Myocardial Infarction or Nonfatal Stroke
Neal B et al – N Engl J Med 2017
EMPA-REG CANVAS Program
-14 % -14 %
Zinman B, et al. N Engl J Med 2015;373:2217–2128
~7.000 patients 100% in 2nd prevention
~10.000 patients 65% in 2nd prevention
-22%
SGLT2i versus OGLD Major results: MACE*, HHF & All cause death
68,490 48,206 24,633 14,987 6553
22,830 15,982 8150 4792 2233
Kaplan–Meier curves for MACE. SGLT2i results driven by >90% dapagliflozin *Defined as cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke. †Defined as an inpatient or outpatient visit with a main diagnosis of heart failure.
SGLT2 inhibitor Other GLD
Weighted means of
hazard ratios No of event
s
Rate/100 P-Y
No of event
s
Rate/100 P-Y
Hazard ratio
P-value
MACE* 339 1.64 1349 2.12 0.78 <0.0001
CV death 56 0.27 340 0.53 0.53 <0.0001
Non-fatal
MI 161 0.78 574 0.90 0.87 0.112
Non-fatal Stroke 144 0.70 514 0.80 0.86 0.113
HHF† 224 0.98 984 1.40 0.70 <0.0001
All-cause
death 289 1.05 1768 2.09 0.51 <0.0001
Strong driver of the MACE: Reduction of 47% in CV death
75% in primary prevention
47%
ADA, Diabetes Care, 2018
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
Antihyperglycemic Therapy in Adults with T2DM
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
Antihyperglycemic Therapy in Adults with T2DM
• SH 2e generation • Pioglitazone • DPP-4 inhibitors • Agonists GLP-1 • SGLT-2 inhibitors • Insulin basal
except contra-indications
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85
Antihyperglycemic Therapy in Adults with T2DM
• Agonists GLP-1 (liraglutide) • SGLT-2 inhibitors • (empa, cana)
except contra-indications
Traitement…
Mécanismes effets métaboliques et cliniques effet diurétique déplétion volémique glucagon
?
Ferrannini et al, 2016
Bénéfice CV indépendant de l’évolution HbA1c, TA, poids, lipides, rein, EASD,2017
Tubulo-glomerular Feedback
1. Cherney DZ Circulation 129(5):587-97, 2014