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 &lt; 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”