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Désordres lipidiques
chez le patient diabétique de type 2
Actualités
Pr Paul VALENSI
Service d’Endocrinologie Diabétologie Nutrition, Hôpital Jean Verdier, Bondy
Service d’Endocrinologie Diabétologie Métabolisme, Hôpital Avicenne, Bobigny
SSR Nutrition Obésité, Hôpital René Muret, Sevran
Université Paris Nord
Disclosure
• Speaches for Merck Santé, GlaxoSmithKline (GSK), Hikma, Merck Sharp Dohme (MSD),
Novo Nordisk, Novartis, Pierre Fabre, Abbott, Eli-Lilly, Bayer, Bristol Myers Squibb (BMS)-
AstraZeneca (AZ)
• Research grants from Merck Santé, GSK, Novo Nordisk, Bayer, Abbott, BMS-AZ
• Participation to Expert Committees for: GSK, Novo Nordisk, Boehringer Ingelheim,
Astra Zeneca, BMS, Daiichi-Sankyo, Lilly
• Expert for HAS and AFSSAPS in France
• Member of R3I consortium (Reduction of Residual Risk)
• Member of the Task Force on Diabetes, Prediabetes and CVD of the ESC in
collaboration with EASD
Principales anomalies lipidiques
chez les diabétiques
Diabète de type 2 - augmentation modérée des triglycérides
- baisse du HDL-cholestérol
- accumulation des lipoprotéines résiduelles enrichies en cholestérol
- Modifications qualitatives avec particules LDL athérogènes : excès de LDL
petites et denses et glycation de l’apolipoprotéine B
Conséquences : plus grande susceptibilité à l’oxydation, épuration plasmatique
réduite et plus grande « rétention » dans paroi artérielle
Diabète de type 1 - Anomalies quantitatives rares
- Anomalies qualitatives fréquentes : + grande athérogénicité des particules
LDL et diminution du pouvoir anti-athérogène des particules HDL
Stratégie hypolipémiante dans le DT2
• Abaisser le LDL-C
• Gérer les autres désordres lipidiques:
TG, non HDL-c
Stratégie hypolipémiante dans le DT2
• Abaisser le LDL-C
• Gérer les autres désordres lipidiques:
TG, non HDL-c
CTT Collaboration. Lancet 2008;371:117–125
Effects on major vascular events of
1 mmol/L reduction in LDL-C (0,40 g/l)
Patients with or without diabetes from 14 RCTs
979 (10.5%)
3441 (9.6%)
4420 (9.8%)
627 (6.7%)
2807 (7.9%)
3434 (7.6%)
501 (5.4%)
1116 (3.2%)
1617 (3.7%)
1782 (19.2%)
6212 (17.4%)
7994 (17.8%)
Control
Major vascular event and prior diabetes
Major coronary event
Diabetes
No diabetes
Any major coronary event
Coronary revascularisation
Diabetes
No diabetes
Any coronary revascularisation
Stroke
Diabetes
No diabetes
Any stroke
Major vascular event
Diabetes
No diabetes
Any major vascular event
1465 (15.6%)
4889 (13.7%)
6354 (14.1%)
407 (4.4%)
933 (2.7%)
1340 (3.0%)
491 (5.2%)
2129 (6.0%)
2620 (5.8%)
776 (8.3%)
2561 (7.2%)
3337 (7.4%)
Treatment
0.78 (0.69-0.87)
0.77 (0.73-0.81)
0.77 (0.74-0.80)
0.75 (0.64-0.88)
0.76 (0.72-0.81)
0.76 (0.73-0.80)
0.79 (0.67-0.93)
0.84 (0.76-0.93)
0.83 (0.77-0.88)
0.79 (0.72-0.86)
0.79 (0.76-0.82)
0.79 (0.77-0.81)
RR (CI)
0.5 0.0 1.5 Treatment better Control better
Events (%)
RR (99% CI)
RR (95% CI)
Similar benefit of statins in the diabetic population
For one mmol/l decrease of LDL-C
CTT Collaboration
Lancet 2010; 376(9753): 1670–1681
Efficacité des statines selon la dose quotidienne
Statine (mg) 5 10 20 40 80
Fluvastatine 10% 15% 21% 27% 33%
Pravastatine 15% 20% 24% 29% 33%
Lovastatine — 21% 29% 37% 45%
Simvastatine 23% 27% 32% 37% 42%
Atorvastatine 31% 37% 43% 49% 55%
Rosuvastatine 38% 44% 51% 58% —
Yusuf et al. NEJM 2016
MACE-3: 3.7 vs 4.8%; HR=0.76
HOPE 3: Blood-Pressure and Cholesterol Lowering
in Persons without Cardiovascular Disease 12 705 femmes et hommes, âgés de ≥ 65 ans et ≥ 55 ans, sans atcd cv, avec ≥ 1 facteur de risque cv
Rosuvastatine 10 mg/ j ou un placebo et l’association candesartan/hydrochlorothiazide 16/12,5 mg/ j
ou placebo (plan factoriel 2x2)
Risque de diabète sous statine vs placebo
Selon la statine
OR 1,09
Le traitement de 255 (95% CI 150–852) patients par statines pendant 4 ans
s’accompagne d’un cas supplémentaire de diabète
Sattar et al. Lancet 2010; 375: 735–42
Après un SCA
Scatter plot with best fit line of major lipid trials (statin and nonstatin trials)
for both primary and secondary prevention of coronary heart disease events
IMPROVE-IT EZ10/Sim40 . IMPROVE-IT EZ10/Sim40 .
Raymond et al. Cleve Clin J Med 2014;81:11-19
-25% pour 1 mmol/l
Gaede P et al. N Engl J Med 2008;358:580-91
Macrovascular complications
The STENO 2 Study - 13.3 yrs Follow-up
- 59% RR but this lets a 40%
residual risk
Statins upregulate the expression
of the LDL receptor and PCSK9
Statins
Transcription factor
Urban et al. JACC 2013;62:1401-1408
Statins upregulate the expression
of the LDL receptor and PSK9
Statins
Transcription factor
LDL-C
decreases
Effect of PCSK9
inhibition
Urban et al. JACC 2013;62:1401-1408
48-week efficacy of evolocumab + standard of care vs standard of care
on % changes in lipids from baseline in EU subjects with and without T2D
190 T2Ds and 1612 non diabetics
Sattar, Valensi, Preiss et al. Poster EASD 2016
ODYSSEY DM-dyslipidemia
Alirocumab chez DT2 avec dyslipidémie mixte incluant non-HDL élevé
Endpoint principal: non-HDL à 24 semaines vs LLT
Endpoint secondaire: vs différents hypolipémiants
Muller-Wieland et al. Cardiovasc Diabetol 2017;16:70
Ray et al. DOM 2018;20:1479-89
Supériorité de l’alirocumab après 24 semaines de traitement
Etude FOURIER: forte réduction du LDL-C sous evolocumab
Patients avec histoire cv dont 35% diabétiques
Réduction du LDL-C
Sabatine et al. NEJM 2017. Giugliano et al. Lancet 2017;390:1962-71
Réduction du RCV
Réduction de évènements cv sous evolocumab
L’étude FOURIER
Sabatine et al. NEJM 2017. Giugliano et al. Lancet 2017;390:1962-71
MACE-3
Effet de l’evolocumab sur le critère principal
chez diabétiques et non diabétiques
L’étude FOURIER
Sabatine et al. NEJM 2017. Giugliano et al. Lancet 2017;390:1962-71
Schwartz et al. NEJM 2018
Composite endpoint: cv death, non fatal MI or stroke,
unstable angina requiring hospitalisation
Diabète incident sous iPCSK9
• Meta-analysis of phase 2/3 randomized clinical trials (RCTs) assessed PCSK9i
versus placebo in the primary hypercholesterolemia setting
• 68,123 participants (20 RCTs) with median follow-up of 78 weeks
• PCSK9i increased fasting blood glucose: mean difference 0,02 g/l
• Incidence of diabetes: RR 1.04 [0.96-1.13]; P = 0.427
De Carvalho LSF et al. Diabetes Care 2018;364
Stratégie hypolipémiante dans le DT2
• Abaisser le LDL-C
• Gérer les autres désordres lipidiques:
TG, non HDL-c
Effets lipidiques d’une forte dose d’atorvastatine
Etude TNT
© Mylan 2015
GLCHO150009(1)
aDefined as CVD and DM and/or SCORE ≥5%; bDefined as SCORE <5%
Prevalence of atherogenic dyslipidaemia
AD is a highly prevalent condition, even in statin-treated patients
Elevated TG and/or low HDL-c are persistent in statin treated patients, including those with DM
Proportion of patients with TGs or HDL-c abnormalities
in the DYSIS study (Dyslipidemia International Study)
Patients
, %
Low HDL-c
(<1.0/1.2 mmol/L
[men/women])
(N=20 388)
Elevated TGs
(≥1.7 mmol/L)
(N=20 489)
a b
Leiter LA et al. Diabet Med 2011; 28: 1343-51
© Mylan 2015
GLCHO150009(1) Kearney et al. 2008
Lipid abnormalities and CV risk
Low HDL-c levels are associated with higher rate of CV events
Rate of major vascular events
in patients with diabetes2
Events
, %
Baseline HDL-c concentration
CTT collaboration meta-analysis on individual participant data from 14 randomised statin trials
(N=18 686 patients with diabetes)
Atherogenic dyslipidemia: HDL-C < 0.88 mmol/l and TG > 2.3 mmol/l
Mean LDL-C 80 mg/dl (2.0 mmol/l)
ACCORD LIPID
MACE: cv death, non fatal MI, non fatal stroke
0
10
15
20
5
10.11
Without AD
+70% 17.32
ACCORD Study Group. NEJM 2010;362:1563-74
With AD
%
© Mylan 2015
GLCHO150009(1)
Lipid abnormalities and CV risk
Non-HDL-c as the emerging target for the treatment of CV risk
Expert consensus1
Non-HDL-c should be used as a marker and target for treatment of residual CV risk in patients with AD
Non-HDL cholesterol accounts for all
atherogenic lipoproteins1,2 • Non-HDL-c may be a better marker of CV risk than LDL-c in
patients with high TGs and diabetes, metabolic syndrome or
chronic kidney disease
• Non-HDL-c is recommended as a secondary target in the
EAS/ESC guidelines
‒ Target levels = LDL-c goal + 0.8 mmol/L (30 mg/dL)
Anti-atherogenic lipoprotein Atherogenic lipoproteins
HDL-c LDL-c VLDL IDL
Calculating non-HDL-c
non-HDL-c = TC – HDL-c
1. Aguiar et al. 2015; 2. Reiner et al. 2011
© Mylan 2015
GLCHO150009(1)
Lipid abnormalities and CV risk
Non-HDL-c as the emerging target for the treatment of CV risk
Meta analysis of statins trials
LDL-c Non-HDL-c
≥2.6 mmol/L
(≥100 mg/dL)
≥3.4 mmol/L
(≥130 mg/dL)
≥2.6 mmol/L
(≥100 mg/dL)
<3.4 mmol/L
(<130 mg/dL)
<2.6 mmol/L
(<100 mg/dL)
≥3.4 mmol/L
(≥130 mg/dL)
Increased CV risk in patients achieving LDL-c levels but not non-HDL-c levels
Increased risk of major CV events compared with reference (LDL-c <2.6 mmol/L [100 mg/dL]
and non-HDL-c <3.4 mmol/L [130mg/dL])
Patients who achieved target LDL-c levels had a 32% increased risk of CV events
if they had not attained non-HDL-c target levels
21%
2%
32%
Boekholdt et al. 2012
In T2Ds with LDL-C < 130 mg/dl atherogenic dyslipidemia is
associated with a 2-3 fold increased risk of silent coronary disease 1080 asymptomatic T2Ds with a normal ECG and ≥ 1 cv risk factor were tested by stress
myocardial scintiscan and coronary angiography if silent ischemia on scintiscan
Valensi et al. Cardiovascular Diabetol 2016
Statines, Fibrates et Lipides
HDL-C
TG
LDL-C
STATINES FIBRATES
The addition of fenofibrate to a statin in T2Ds still having AD:
a way to reduce the residual risk
Results confirmed in ACCORDION (post-trial follow-up)
ACCORD LIPID
0
10
15
20
5
10.11
Without AD
+70% 17.32
ACCORD Study Group. NEJM 2010;362:1563-74
- 31% RRR 4.95% ARR
12.37
Simvastatine + Fenofibrate
10.11
With AD
MACE-3
ACCORD Lipid
Bonne tolérance de la simvastatine et de l’association au fénofibrate
Laboratory Measures, no. (%)
Simvastatin +
Fenofibrate
(N=2765)
Simvastatin +
Placebo (N=2753) p value
ALT ever > 3X ULN 52 (1.9%) 40 (1.5%) 0.21
ALT ever > 5X ULN 16 (0.6%) 6 (0.2%) 0.03
CK ever > 5X ULN 51 (1.9%) 59 (2.2%) 0.43
CK ever > 10X ULN 10 (0.4%) 9 (0.3%) 0.83
Serum creatinine elevation
Women ever > 1.3 mg/dL
Men ever > 1.5 mg/dL
235 (28%)
698 (37%)
157 (19%)
350 (19%)
<0.001
<0.001
ACCORD Study Group. N Engl J Med March 14, 2010.
Meta-analysis of fibrate trials in subjects
with (n=2428) and without (n=2298) dyslipidemia
Subgroups with dyslipidemia
ACCORD lipid criteria TG ≥ 2.30 mmol/L (2 g/l), HDL-C ≤ 0.88 mmol/L (0.4 g/l)
Sacks et al. NEJM 2010; 363: 692-694
© Mylan 2015
GLCHO150009(1) Sacks et al. Circulation 2014;129:999-1008
Low HDL-c and elevated TGs can lead to microvascular complications
OR for microvascular complications associated with a quintile increase in TGs or HDL-c
0,5 1 1,5
REALIST:
2535 patients with
T2DM who had diabetic
kidney disease, diabetic
retinopathy or both
complications, and
3683 matched controls,
in 13 countries
with LDL-C <130 mg/l
Kidney disease or retinopathy
Kidney disease
Retinopathy
OR (95% CI) for adjacent TG quintiles
(0.5 mmol/L [44 mg/dL])
0,5 1 1,5
OR (95% CI) for adjacent HDL-c quintiles
(0.2 mmol/L [7.7 mg/dL])
TGs HDL-c
Elevated TGs and low levels of HDL-c were significantly associated with kidney disease
1.18 (1.11, 1.22) 0.92 (0.88, 0.96)
1.2 (1.13, 1.28) 0.92 (0.87, 0.97)
1.04 (0.98, 1.11) 0.97 (0.9, 1.05)
ACCORD EYE Effects of combination therapy by fenofibrate with simvastatin
on diabetic retinopathy
NEJM 2010
Etudes en cours chez patients avec hypertriglycéridémie
• STRENGTH: EpaNova
• PREMINENT: pemafibrate chez diabétiques
• REDUCE-IT: omega 3 (icosapent Ethyl)
PROMINENT study Pemafibrate: un modulateur de PPAR-α
Pradhan et al. Am Heart J 2018;206:80-93
Efficacité du pemafibrate sur TG et HDL-C
chez des patients avec la TG élevés avec HDL-C bas
JC Fruchart. Cardiovasc Diabetology 2017;16:124
• EPA hautement purifié: 4 g/jour
• Chez patients en prévention secondaire ou diabétiques avec autres fdr
• Sous statines
• LDL-C 0,41 à 1 g/l
• TG 1,35 à 4,99 g/l
• Sous EPA, réduction de 18% des TG (-0,39 g/l)
Bhatt et al. NEJM 2018
Bhatt et al. NEJM 2018
MACE extended
MACE 3
Bhatt et al. NEJM 2018
Recommandations de l’ESC-EAS 2011
pour le traitement des dyslipidémies chez les diabétiques
Reiner et al. Eur Heart J 2011;32:1769-1818
Objectif LDL-C Objectifs
secondaires
DT1 en présence d’une
microalbuminurie et d’une maladie
rénale
Réduire d’au moins
30%
avec une statine
DT2 avec maladie cv ou rénale
et DT2 sans maladie cv âgés de >40ans
ayant ≥1 fdr cv ou des marqueurs
d’atteinte des organes cibles
< 0,7 g/l Non-HDL-C < 1 g/l
Apo B < 0,8 g/l
Tous les DT2 < 1 g/l Non HDL-C < 1,30 g/l
Apo B < 1 g/l
Triglycérides: chez les patients à haut RCV ayant des TG > 2 g/l
malgré les mesures d’hygiène de vie, fibrates recommandés
Catapano et al. ESC/EAS guidelines 2016
Catapano et al. ESC/EAS guidelines 2016
Nephropathy, preproliferative retinopathy
Diabetes Metab 2016
LDLc concentrations in this figure are thresholds for intervention or intensification,
as well as the minimum target to be achieved
Management from triglycerides levels
LOOK AHEAD
Wing et al. Diabetes Care 2011;34:1481
Statin + ezetimibe: second
LDL-C: the lower the better
CETP inhibitor : no
PCSK9 inhibitor : the future
Statin first
Omega-3 : purified EPA ?
Fibrate: in some cases
Fenofibrate + Statin : possible
Diabète et lipides
Statégie thérapeutique
