complications chroniques du diabète · 2018. 9. 5. · cv disease is the single leading cause of...

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Principalecaused’insuffisancerénaleterminale:

±10%décèdentd’insuffisancerénale

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Affections cardiovasculaires risque 2x plus élevé

Augmenta#ondelamortalitécardiovasculaireetdesAVC

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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.

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.


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.


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.


-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


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


- EMPA-REG OUTCOME

Fonction cumulative-incidence. HR, hazard ratio



Décès cardiovasculaires

BE/DIA/00069a 05/2017


- EMPA-REG OUTCOME

Fonction cumulative-incidence. HR, hazard ratio


Hospitalisation pour insuffisance cardiaque


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



• SH 2e generation • Pioglitazone • DPP-4 inhibitors • Agonists GLP-1 • SGLT-2 inhibitors • Insulin basal

except contra-indications



• 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

complications chroniques du diabète · 2018. 9. 5. · cv disease is the single leading cause of...

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