Gerald Tomkin , Director of the Diabetes Institute Beacon Hospital
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Diabetes, Atherosclerosis and cholesterol
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Gerald Tomkin , Director of the Diabetes Institute Beacon Hospital
- 1. Diabetes atherosclerosis and cholesterol Gerald H. Tomkin
- 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
- 3. LPL Macrophage LDL Glycated LDL LPL LDL Oxidised LDL Atherosclerosis Oxidised LDL antibodies VCAM ICAM TRL Inflammation (Neutrophil)cytokines metaloproteinases macrophage Smooth Muscle cells CRP? Fig 1
- 4. 3210 0 10 20 30 40 50 Non-diabetic Diabetic Mortality/1000persons 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
- 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,
- 13. Suicide or Homicide? The side effect of statins Get down from there, the neigbours are looking!
- 14. Intestine ACAT HMGCoA reductaseMTP Chylomicron Apo B48 Apo B48 ABCG5/G8 HMGCoA reductase MTP ACAT Apo B100 Bile Cholesterol VLDL Apo B100 LPL Niemann Pick C1Like 1 LDL ABCG5/G8 Chylomicron synthesis Triglyceride Cholesterol Phospholipid
- 15. DiabetesControl p<0.05 0 0.5 1 1.5 NPC1-L1mRNA NPC1-L1 in diabetic and control subjects Lally S, et al. Diabetologia 2006;49;1006–1008.NPC1-L1: Niemann-Pick C1-Like 1.
- 16. IMPROVE-IT trial Primary 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.
- 17. intestine MTP triglyceride Dietary cholesterol phospholipid chylomicron Triglyceride Cholesterol phospholipidApo B48 Apo B48 MTP MTP Apo B100 VLDL Apo B100 LDL
- 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
- 24. Le déjeuner sur l'herbeRenoir
- 25. Liver MTP ApoB100 VLDL HMGCoA reductase Statin NPC1-L1 Cholesterol excretion Apo B synthesis inhibitor Cholesterol synthesis Bile duct Apo B synthesis inhibition
- 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
- 27. LDL receptor Coated pit LDL LDL PCSK9 LDL receptor Lysosome Lysosome trafficking of the LDL receptor
- 29. 2002 Angina 2002 Hypertension Dyslipidaemia 2008 Diabetes Transient ischaemic attack Right carotid stenosis >75% Cholesterol 8 mmol/l LDL cholesterol 5.2 mmol/l 2011 Carotid endarterectomy 2013 Myocardial infarction Coronary 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/l HDL cholesterol 1.06 mmol/l Patient case: DOB 9/7/56, Age 48
- 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”
Notas del editor
- 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.