Diabetes atherosclerosis and cholesterolGerald H. Tomkin
Disclosures
• Very small grants from Lilly, Novo Nordisk, Bayer, AstraZeneca, Johnson and Johnson, Merck
• Small stock holdings in Sanofi Aventis, GlaxoSmithKline, Ionis, Malin Corp, Allergan
LPL
MacrophageLDL
Glycated LDL
LPL LDL
Oxidised LDL
Atherosclerosis
Oxidised LDL antibodies
VCAM ICAM
TRL
Inflammation (Neutrophil)cytokines metaloproteinases
macrophage
Smooth Muscle cells
CRP?
Fig 1
32100
10
20
30
40
50
Non-diabetic
Diabetic
Mor
talit
y/10
00 p
erso
ns
Lowe LP, et al. Diabetes Care. 1997;20(2):163–169.
Number of risk factors
Effect of three major risk factors (hypercholesterolaemia, smoking and diastolic hypertension) on age-standardised
cardiovascular disease mortality
Haffner SM, et al. N Engl J Med 1998;339;229–234.
Probability of death from CHD in 1059 NIDDM and 1378 non-diabetic subjects
ESC/EASD guidelines
• Very high-risk DM + at least one other risk factor– LDL cholesterol <1.8
• High-risk DM alone– LDL cholesterol <2.5
Ryden L, et al. Eur Heart J 2013;34:3035-3087.
Cannon CP, et al. J Am Coll Cardiol. 2006;48:438–445.
Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy
• 27,548 patients enrolled in four large trials
• 16% odds reduction of coronary death or any cardiovascular event (p<0.00001)
The effect of cholesterol-lowering therapy on major vascular events
Alas! Even with treatment, 20%developed major vascular events
Heart Protection Study Collaborative Group. Lancet 2003;361;2005–2017.
Log rank p<0.0001
Placebo-allocated
Simvastatin-allocated
Benefit (SE) per 1000 allocated simvastatin
–1 (6) 13 (8) 34 (9) 47 (10) 58 (48)Years of follow-up
Maj
or v
ascu
lar e
vent
s (%
)
51 (15)
Risk of CHD by dyslipidaemia status in women and men with DM and LDL-C <2.58mmol/l
Rana JS, et al. Am J Cardiol. 2015;116:1700–1704.
HDL-C normalTG normal
N=7278
HDL-C normalTG highN=4484
HDL-C lowTG normal
N=4048
HDL-C lowTG high
N=12,508
Women
MenHaz
ard
ratio
• NCEP ATP III guidelines – Only 66% of patients with very high cardiovascular
risk achieve their lipid targets
• ESC/EAS guidelines – Only 25% of patients with very high cardiovascular
risk achieve their lipid targets
Lipid target achievement among patients with very high cardiovascular risk in a lipid clinic
Barkas F, et al. Angiology. 2015;66(4):346–353.
Cardiovascular Risk Factor Targets and Cardiovascular Disease Event Risk in Diabetes: A Pooling Project of the Atherosclerosis Risk in Communities Study, Multi-Ethnic
Study of Atherosclerosis, and Jackson Heart Study.
Wong et al diabetes care 2016,
Targets reached
Blood pressure 42%LDL 33%HbA1C 42%
1 target 41% 2 targets 26.5%3 targets 7%
Risk Reduction
• 1 Target 36%
• 2 Targets 52%
• 3 targets 62%
Conclusion 1.achievement of targets uncommon!2.Achieving targets substantially reduces risk
Wong et al diabetes care 2016,
Suicide or Homicide?The side effect of statins
Get down from there, the neigbours are looking!
Intestine
ACAT HMGCoA reductaseMTP
Chylomicron
Apo B48
Apo B48
ABCG5/G8
HMGCoA reductase
MTP
ACAT
Apo B100
BileCholesterol
VLDL
Apo B100
LPL
Niemann Pick C1Like 1
LDL
ABCG5/G8
Chylomicron synthesis
TriglycerideCholesterolPhospholipid
DiabetesControl
p<0.05
0
0.5
1
1.5
NP
C1-
L1 m
RN
A
NPC1-L1 in diabetic and control subjects
Lally S, et al. Diabetologia 2006;49;1006–1008.NPC1-L1: Niemann-Pick C1-Like 1.
IMPROVE-IT trialPrimary endpoint by 1 month pre-specified LDL-C and hs-CRP target achievement
Bohula EA, et al. Circulation. 2015;132:1224–1233.hs-CRP: High-sensitivity C-reactive protein..
intestine
MTP
triglyceride
Dietary cholesterolphospholipid
chylomicron
TriglycerideCholesterolphospholipidApo B48
Apo B48
MTP
MTPApo B100
VLDL
Apo B100
LDL
Fig. 1. Intestinal MTP mRNA levels in type 2 diabetic (black) and non-diabetic (white) subjects on statin therapy and not treated with statins. Data is expressed as amol/μg total RNA (mean ± S.D.). *p < 0.05 compared to non-diabetic subjects .
Catherine Phillips, Karen Mullan, Daphne Owens, Gerald H. Tomkin Atherosclerosis, Volume 187, Issue 1, 2006, 57–64
MTP expression in diabetic and control subjects
Effect of MTP inhibitor – Lomitapide - on plasma lipids and lipoproteins
Cuchel M, et al. Lancet. 2013;381(9860):40–46.
Study week
Cha
nge
from
bas
elin
e (%
)
Cuchel M, et al. Lancet. 2013;381(9860):40–46.
Effect of MTP inhibitor lomitapibe on ALT AST and liver fat
Apo C111 defender of delipidation
Apo B100
LPL
O2
apo C 111
LDL particle
LDL containing apoC3 and risk of CHD
Mendivil CO, et al. Circulation. 2011;124:2065–2072.
Gaudet D et al. N Engl J Med. 2015;373:438–447.
Antisense inhibition with Volanesorsen of apoC3 in patients with hypertriglyceridaemia
Le déjeuner sur l'herbe Renoir
Liver
MTP
ApoB100
VLDL
HMGCoA reductase
Statin
NPC1-L1
Cholesterol excretion
Apo B synthesis inhibitor
Cholesterol synthesis
Bile duct
Apo B synthesis inhibition
Long-term efficacy and safety of apo B inhibition with Mipomersen in patients with familial hypercholesterolaemia:
2-year interim results of an open-label extension
Santos RD, et al. Eur Heart J. 2015;36(9):566–575.
N=141 130 111 66 53
LDL-C Apo B Lp(a)
Baseline Week 26 Week 52 Week 76 Week 104-40
-35
-30
-25
-20
-15
-10
-5
0
% C
hang
e fr
om b
asel
ine
Timepoint
LDL receptor
Coated pitLDL
LDLPCSK9
LDL receptor
Lysosome
Lysosome
trafficking of the LDL receptor
2002 Angina
2002 HypertensionDyslipidaemia
2008 Diabetes Transient ischaemic attackRight carotid stenosis >75%
Cholesterol 8 mmol/lLDL cholesterol 5.2 mmol/l
2011 Carotid endarterectomy
2013 Myocardial infarctionCoronary artery bypass graft
2014 Atorvastatin 80 mg Ezetimibe 10 mg Fenofibrate 290 mg/day Cholestagel 4.3g/day
LDL cholesterol 3.9 mmol/l
July 2015 Alirocumab 75 mg every 2 weeks
March 2016 LDL cholesterol 0.09 mmol/lHDL cholesterol 1.06 mmol/l Cholesterol 3.0 mmol/l
Patient case: DOB 9/7/56, Age 48
LAPLACE-TIMI 57 trial: PCSK9 inhibitor + statin
Desai NR, et al. J Am Coll Cardiol. 2014;63(5):430–433.
Lipinski MJ, et al. Eur Heart J 2016;37:536–545.
Incidence of all-cause mortality (A), CV death (B) and CV events (C) with PCSK9 inhibitors or ezetimibe
Event 101 mg/dl
HeFH 127 mg/dl
Intolerant 123 mg/dl
Last LDL-C >70 mg/dlWhole cohort n = 734 (100%)
HeFH n = 734 100%CVD event n = 180 (25%)Statin intolerance n = 179 (24%)
Irrespective of statin intolerance
HeFH alone 23%CVD event alone 20%HeFH and/or CVD event 48%
LDL-C <100 n = 134LDL-C >100 n = 220
PCSK9 treatment eligible 30%
Glueck CJ, et al. Lipids Health Dis. 2016;15(1):55.
Heterozygous familial hypercholesterolaemia (HeFH)
The exciting future
We need to work harder to reduce risk factors more intensively
Conclusion
Thank you for listening and as Maureen Potter used to say “If you enjoyed the talk, tell your friends and if not save your breath to cool your porridge”
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