2. 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
5. 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
6. 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
7. 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)
8. 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–
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
Majorvascularevents(%)
51 (15)
9. 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 normal
TG normal
N=7278
HDL-C normal
TG high
N=4484
HDL-C low
TG normal
N=4048
HDL-C low
TG high
N=12,508
Women
Men
Hazardratio
10. • 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.
11. 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%
12. 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,
18. 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
19. Effect of MTP inhibitor – Lomitapide - on
plasma lipids and lipoproteins
Cuchel M, et al. Lancet. 2013;381(9860):40–46.
Study week
Changefrombaseline(%)
20. Cuchel M, et al. Lancet. 2013;381(9860):40–46.
Effect of MTP inhibitor lomitapibe on ALT
AST and liver fat
21. Apo C111 defender of delipidation
Apo B100
LPL
O2
apo C
111
LDL particle
22. LDL containing apoC3 and risk of CHD
Mendivil CO, et al. Circulation. 2011;124:2065–2072.
23. Gaudet D et al. N Engl J Med. 2015;373:438–447.
Antisense inhibition with Volanesorsen of apoC3 in patients with hypertriglyceridaemia
26. 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
%Changefrombaseline
Timepoint
30. LAPLACE-TIMI 57 trial: PCSK9 inhibitor + statin
Desai NR, et al. J Am Coll Cardiol. 2014;63(5):430–433.
31. 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
32. Event
101 mg/dl
HeFH
127 mg/dl
Intolerant 123 mg/dl
Last LDL-C >70 mg/dl
Whole 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 = 134
LDL-C >100 n = 220
PCSK9 treatment eligible 30%
Glueck CJ, et al. Lipids Health Dis. 2016;15(1):55.
Heterozygous familial
hypercholesterolaemia (HeFH)
34. 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”
Editor's Notes
Disclosures
Disclosures
Forrest plots comparing the incidence of all-cause mortality (A), cardiovascular death (B), and cardiovascular events (C) for patients randomized to proprotein convertase subtilisin-kexin type 9 serine protease inhibitors or ezetimibe. Data are presented with odds ratios and 95% confidence intervals.