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Diabetic dyslipidemia : The pro- atherogenic role of CETP and future use of CETP inhibitors

Diabetic dyslipidemia : The pro- atherogenic role of CETP and future use of CETP inhibitors. Prof. John Betteridge University College London United Kingdom. Diabetes and Cardiovascular Disease: Time To Act!.

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Diabetic dyslipidemia : The pro- atherogenic role of CETP and future use of CETP inhibitors

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  1. Diabetic dyslipidemia: The pro-atherogenic role of CETP and future use of CETP inhibitors Prof. John Betteridge University College London United Kingdom

  2. Diabetes and Cardiovascular Disease: Time To Act! “With the rising tide of diabetes around the globe, the double jeopardy of diabetes and cardiovascular disease is set to result in an explosion of these and other complications- unless preventive action is taken.” Prof Sir George Alberti, IDF President. International Diabetes Federation

  3. Risk of Fatal and Non-fatal CHD in Menwith Type 2 Diabetes *Adjusted on age, smoking, alcoholconsumption,social class, BMI, physicalactivity and previous stroke;** Furtheradjustment on riskfactors Prospective follow-up of 4045 men 60 to 79 years 379 major CHD events Comparison of late (>60 years) versus early onset diabetes (<60 years) Vannamethee SG et al. ArchIntern Med 2011.

  4. 26.5 84.5 14.2 32.9 132.3 24% 17.5 57% 23% 9.4 14.1 15.6 50% 22.5 44% 1.0 1.3 30% Numbers of People (106) with Diabetes for 2000 and 2010 Incidence in 2000 Incidence in 2010 % increase from 2000 to 2010 World 2000:151 million 2010:221 million (+46%) Adapted from Amos AF et al Diabet Med 1997;14:S7-S85.

  5. Survival Post-MI in Diabetic and Non-diabetic Men and Women 100 90 80 70 60 50 40 0 100 90 80 70 60 50 40 0 Women Men (n=1628) (n=568) Survival (%) Survival (%) (n=156) (n=228) 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80 Months post-MI Months post-MI Diabetes No diabetes Sprafka JM et al Diabetes Care 1991;14:537.

  6. Temporal Mortality Trends Patients with and without Diabetes Suffering a Myocardial Infarction (a comparison of 1762 patients in 1995 with 1642 patients in 2003) Cubbon RM et al. Eur Heart J 2007; 28: 540–545

  7. Plaque Characteristics Plaque burden increased in diabetic subjects and distal burden increased in type 2 Mean percent necrotic core greater in type1 (p=0.05) and type 2 (p=0.004) Macrophage plaque area and T cell infiltration greater in diabetic subjects (p=0.03) Mean number of fibrous cap atheromas greater in type 2 ( p<0.02) Healed plaque ruptures greatest in type 1 and type 2 Burke et al ATVB, 2004; 24: 1266

  8. UKPDS:Risk Factors for MI. • LDL cholesterol • HDL cholesterol • HbA1c • Systolic blood pressure • Smoking Baseline Epidemiology Data Turner et al BMJ 1998

  9. AtherogenicDyslipidaemia( Metabolic Syndrome, Type 2 Diabetes) Triglycerides Insulin resistance Small, dense LDL Remnants HDL2

  10. Clinical Manifestations of Central Obesity • Type 2 diabetes dysglycaemia • Dyslipidaemia • low HDL • small, dense LDL • hypertriglyceridaemia • Hypertension • Endothelial dysfunction Inflammation (hsCRP) • Impaired thrombolysis •  PAI-1 Insulin resistance FFAs Adiponectin CentralObesity Courtesy of Selwyn AP, Weissman PN.

  11. Lipoprotein Metabolism in Insulin Resistance and Type 2 Diabetes Adipose tissue LDL profile by electrophoresis ADIPONECTIN NEFA Normal TG CE LDL VLDL Lipoprotein lipase Pattern A CE CETP ElevatedTRL TG TG-rich Chylomicrons TG CE LDL Plasma Triglycerides (mmol/l) Hepatic lipase 4 4 Intestine Small, dense LDL 2 Type 2 diabetesControls Pattern B 0 6 0 2 4 9 12 24 Hours

  12. Characteristics of LDL Subclasses Large, buoyant LDL pattern A Small, dense LDL pattern B GAG-binding segments (3147–3157) (3359–3367) Phospholipids Free cholesterol apo B-100 • Polar lipids: 63.3% • Accessible apo B-100: 36.7 • Low GAG affinity • Polar lipids: 35.6% • Accessible apo B-100: 64.4 • High GAG affinity Hurt-Camejo E et al Curr Opin Lipidol 2000;11:465

  13. Apo B More apo B The Absolute Concentration of LDL-C Can be Misleading in Subjects with Small, Dense LDL. Large, buoyant particles Small, dense particles At the same LDL-C level, the number of LDL particles is increased, if small and dense Each LDL particle contains one molecule of apo B Apo B concentration increases in direct relation to number of LDL particles Sniderman AD et al Ann Intern Med 2001

  14. LDL Subfractions “Control” vs Patient with Insulin Resistance DM-TG 2.95 mmol/l DJB-TG 0.9 mmol/l III I II Increasing density Decreasing size

  15. Statins:The Evidence Base. Continuum of risk High-risk CHD patients (high cholesterol) 4S (simvastatin) Secondaryprevention 22.6 Majority of CHD patients (broad range of cholesterol levels) CARE (pravastatin) LIPID(pravastatin) HPS 12.9 Placebo MI rate per 100 subjects per 5 years 8.44 Patients at high risk of CHD (high cholesterol) 7.9 WOSCOPS (pravastatin) Primaryprevention Patients at low risk of CHD (low HDL-C) 2.8 AFCAPS/TexCAPS (lovastatin)

  16. CARDS:Collaborative AtoRvastatin Diabetes Study Patient Population • Type 2 diabetes (40-75y) • No prior MI or CVD • Other risk factors + • Lipid profile: • LDL-C <159 mg/dL (4.14 mmol/L) • TG <600 mg/dL (6.78 mmol/L) • Collaboration in the UK with Diabetes UK, NHS R&D and Pfizer d/b PBO 2,838Patients Atorvastatin 10 mg 304 events Expected completion 2005 Actual termination June 2003 after 2nd interim analysis 210 events • Primary Endpoint • Time to first major CVD event Colhoun et al. Diabetic Med 2002; 32: 259-264.

  17. Median Lipid Levels by Treatment Total cholesterol (mmol/L) LDL cholesterol (mmol/L) Average difference 40% 1.20 mmol/L (46mg/dL) p<0.0001 Average difference 26% 1.40 mmol/L (54mg/dL) p<0.0001 6 4 3 4 2 2 1 0 0 0 1 2 3 4 4.5 0 1 2 3 4 4.5 Years of Study Years of Study Placebo Atorvastatin

  18. Median Lipid Levels by Treatment Triglycerides (mmol/L) HDL cholesterol (mmol/L) Average difference 19% 0.39 mmol/L, 35mg/dL p<0.0001 Average difference 1% 0.02 mmol/L,0.8mg/dL p=0.0002 1.4 2 1.2 1 .8 1 .6 .4 .2 0 0 0 1 2 3 4 4.5 0 1 2 3 4 4.5 Years of Study Years of Study Placebo Atorvastatin

  19. Cumulative Hazard for Primary Endpoint 15 Relative Risk -37% (95% CI: -52, -17) Placebo 127 events 2.46/100 person yrs P=0.001 10 Cumulative Hazard (%) Atorvastatin 83 events 1.54/100 person yrs 5 0 0 1 2 3 4 4.75 Years Number at risk Placebo 1410 651 1351 1306 305 1022 Atorva 1428 694 1392 1361 328 1074

  20. RRR12% RRR22% RRR19% RRR23% RRR31% 1009 972 5683 5722 519 551 1481 1449 1455 1457 Diabetes + CHD No diabetes + CHD Diabetes + other CVD No diabetes + other CVD Diabetes + no CVD Heart Protection Study Diabetes Subgroups With/Without CHD or Other CVD HPS Collaborative Group. Lancet. 2003;361:2005

  21. LDL-C and change in percent atheroma volume in IVUS studies 2 REVERSAL5 pravastatin 1.5 CAMELOT4 placebo Change in Percent Atheroma Volume*(%) 1 ACTIVATE1 placebo 0.5 A-Plus2 placebo Progression REVERSAL5 atorvastatin 0 50 60 70 80 90 100 110 120 Mean LDL-C (mg/dL) Regression -0.5 ASTEROID3 rosuvastatin -1 †ASTEROID and REVERSAL investigated active statin treatment; A-PLUS, ACTIVATE AND CAMELOT investigated non-statin therapies but included placebo arms who received background statin therapy (62%, 80% and 84% respectively). *Median change in PAV from ASTEROID and REVERSAL; LS mean change in PAV from A-PLUS, ACTIVATE AND CAMELOT 1 Nissen S et al. N Engl J Med 2006;354:1253-1263. 2 Tardif J et al. Circulation 2004;110:3372-3377. 3 Nissen S et al. JAMA 2006;295 (13):1556-1565 4 Nissen S et al. JAMA 2004;292: 2217–2225. 5 Nissen S et al. JAMA 2004; 291:1071–1080

  22. Objective: To characterize IVUS defined coronary atherosclerosis progression in diabetic patients Methods: Systematic analysis, 2,237 subjects in RCTs of atherosclerosis progression, Reversal, Camelot, Activate, Asteroid and Illustrate . All patients had CAD, at least one lumen narrowing >20% on diagnostic arteriogram. The pattern of disease progression was compared in subjects with and without diabetes Diabetic patients had a greater percent atheroma volume 40.2 ± 0.9% vs 37.5 ± 0.8% on multivariate analysis, p<0.0001 at baseline.

  23. AtherogenicDyslipidaemia( Metabolic Syndrome, Type 2 Diabetes) Triglycerides Insulin resistance Small, dense LDL Remnants HDL2

  24. HPS Diabetic CohortBenefits of Simvastatin by Baseline LDL and HDL-Cholesterol 31.1 27.9 25.9 23.3 20.9 21.3 16.8 Placebo Simvastatin 15.7 Vascular Events (%) LDL-Cholesterol 3mmol 3mmol HDL-Cholesterol 0.9mmol 0.9mmol

  25. CETP CE Enrichment with cholesteryl esters Transient enrichment with triglycerides (TG) HDL3 Hepatic Lipase (HL) HL smalldense LDL TG Formation of small HDL3 and lipid-poor pre-HDL Formation of small dense LDL Pre -HDL Facilitated modification of LDL Regeneration of HDL or removal from circulation, e.g. by renal filtration Role of Cholesteryl Ester Transfer Protein (CETP) in Lipoprotein Metabolism VLDL HDL2 Von Eckardstein, Expert Review of Cardiovascular Therapy 2010, 8(3):345–58.

  26. Dysfunctional HDL in Diabetes • ABCA1-mediated cholestrol efflux↓ • LCAT activation↓ • PON1↓ • Anti-oxidative activity↓ • Protection against apoptosis↓ • Stimulation of eNOS/NO↓ • Inhibition of VCAM-1 and ICAM-1 expression↓ • Inhibition of neutrophil infiltration↓ • Stimulation of re-endothelialisation↓ CE TG SAA sPLA2 CETP PAF-AH PAF-AH PAF-AH PON1 PON1 PON1 PON1 A-I A-I SAA PLTP A-I A-I SAA PLTP A-II A-II LCAT A-I LCAT A-I A-I A-I A-II A-I J A-II LCAT PLTP A-I A-I A-I A-I PLTP A-II A-II LCAT A-I A-I A-II A-I PAF-AH CETP CETP sPLA2 CETP Oxidation CETP↑ Glu Glx CE TG CE TG OH OH -NH-CH2-C-CH-CH-CH-CH2OH O OH Nobecourt et al. Diabetologia 2005;48:529; 2007;50:243; 2008;51:1008; ATVB 2010;30:766; DeSouza et al. Atherosclerosis 2008:197:84, Sorrentino et al. Circulation2010, 121:110–122.

  27. How to Increase HDL? Acute: Reconstituted HDL: eg A1 Milano (Arg 173 Cys) (IVUS) Delipidated HDL (IVUS) Apo A1 mimetics (?) Chronic: Diet and lifestyle: Weight reduction, diet, alcohol, exercise, smoking cessation Statins PPAR alpha agonists: fibrates(HHS; VAHIT; BIP; FIELD ACCORD) PPAR gamma agonists: TZDs (PROactive, CHICAGO, PERISCOPE) Dual PPAR Agonist aleglitazar Nicotinic acid (ER form; MK0524) (CDP, Numerous regression trials) CETP inhibitors egtorcetrapib, (ILLUMINATE),dalcetrapib, anacetrapib

  28. ILLUMINATE: Recent Post Hoc Analysis: Mechanism? Barter et al, Circulation 2011; 124: 555–562. • 6661 patients with DM: in torcetrapib/atorvastatin arm vs. atorvastatin arm • significant lower plasma glucose levels: 0.34 mmol/L • significant lower HbA1c levels: 0.1% vs. 0.3% increase • significant lower insulin levels: 11.7 µU/ml • significant lower HOMA: increase in atorvastatin arm

  29. “If treatment with dalcetrapib and anacetrapib is found to be both antidiabetic and cardioprotective, there will be a compelling case for considering CETP inhibition as a treatment of choice in patients with type 2 diabetes mellitus”. • Barter et al, Circulation 2011: (Aug) 124:555-562

  30. How to Increase HDL? Acute: Reconstituted HDL: eg A1 Milano (Arg 173 Cys) (IVUS) Delipidated HDL (IVUS) Apo A1 mimetics (?) Chronic: Diet and lifestyle: Weight reduction, diet, alcohol, exercise, smoking cessation Statins PPAR alpha agonists: fibrates(HHS; VAHIT; BIP; FIELD ACCORD) PPAR gamma agonists: TZDs (PROactive, CHICAGO, PERISCOPE) Dual PPAR Agonist aleglitazar Nicotinic acid (ER form; MK0524) (CDP, Numerous regression trials) CETP inhibitors egtorcetrapib, (ILLUMINATE),dalcetrapib, anacetrapib

  31. Background; Several clinical trials have reported inconsistent findings for the effects of fibrates on CVD risk Methods: Systematic search 1950-2010. Included RCTs assessing the effects of fibrates on CVD outcomes. Summary estimates of relative risk (RR) reductions calculated with random effects model. 18 trials, 45058 participants, 2870 major CVD events, 4552 coronary events and 3880 deaths Results: Fibrate therapy associated with 10% RR reduction (95% CI 0-18; p=0.048) major CVD events 13% RR reduction (95% CI 7-19; p<0.0001 Coronary events No impact on all-cause mortality, CVD mortality or sudden death

  32. How to Increase HDL? Acute: Reconstituted HDL: eg A1 Milano (Arg 173 Cys) (IVUS) Delipidated HDL (IVUS) Apo A1 mimetics (?) Chronic: Diet and lifestyle: Weight reduction, diet, alcohol, exercise, smoking cessation Statins PPAR alpha agonists: fibrates(HHS; VAHIT; BIP; FIELD ACCORD) PPAR gamma agonists: TZDs (PROactive, CHICAGO, PERISCOPE) Dual PPAR Agonist aleglitazar Nicotinic acid (ER form; MK0524) (CDP, Numerous regression trials) CETP inhibitors egtorcetrapib, (ILLUMINATE),dalcetrapib, anacetrapib

  33. Long term Effects of Pioglitazone on HDL-Cholesterol and Triglycerides in CVD Trials Dormandy et al Lancet, 2005; 366: 1279 Mazzone T et al. JAMA, 2006; 296: 2572 Nissen et al JAMA, 2008; 299: 1562

  34. EEM Area LumenArea Intravascular Ultrasound of Coronary Arteries Determining the Atheroma Area Precise planimetry of EEM and lumen bordersallows calculation of atheroma cross-sectional area On multivariate analysis the only parameter independently associated with slowing of disease progression in the Pioglitazone group was Triglyceride/HDL-C ratio P=0.03 (EEM Area — Lumen Area) Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory Nicholls et al JACC 57 No 2 2011

  35. Objective: Will pioglitazone stabilize carotid artery vulnerable plaque in patients with acute coronary syndromes (ACS) and type 2 diabetes. Population: 61 patients with type 2 diabetes, age 63yrs, approx 70% male and echo lucent carotid plaques within 5 days of ACS. Random allocation to pioglitazone 15-30mg/day or matching placebo. Methods: Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated back scatter (IBS) An increase in IBS reflects an increase in plaque echogenicity. Echolucent plaques with low IBS represent identify lipid and macrophage-rich lesions, unstable plaques

  36. Plaque echo lucency using carotid ultrasound with integrated back scatter Pre Treatment Post Treatment for 1 month with Pioglitazone

  37. Aleglitazar Balanced Activation of PPAR- and - 32 24 Fold activation of PPAR- Fold activation of PPAR- 16 8 0 –11 –10 –9 –8 –7 –6 –5 –4 ↑ Roche data on file.

  38. Henry et al. Lancet 2009; 374:126.

  39. The SYNCHRONY Study Effects of Aleglitazar on HbA1c Change in HbA1c from baseline Change in HbA1c from baseline Henry et al. Lancet 2009; 374:126.

  40. The SYNCHRONY Study Effects of Aleglitazar on Lipids and Lipoproteins HDL-Chol Trigs LDL-Chol Apo B Henry et al. Lancet 2009; 374:126.

  41. Aleglitazar Summary of Cardiometabolic Effects Dyslipidemia ↑ HDL 21% ↓ Triglycerides 43% ↓ LDL 16% Inflammation and thrombinolysis/ fibrinolysis ↓ hs-CRP 40% ↓Fibrinogen 10% ↓PAI-1 6% Glycemic control ↓ HbA1c 0.85% ↓ FPG –2.16 mmol/L ↓ HOMA-IR 35% Hypertension ↓Blood pressure 1 to 3 mmHg Henry et al. Lancet 2009; 374:126.

  42. Aleglitazar Ongoing Trial – ALECARDIO Treatment Period (until 950 events) at least 2.5 years 4 weeks Run-in Period 2–6 weeks Follow-up Aleglitazar 150 µg Index ACS Event Placebo Screened Patients Standard of care (diabetes and other CV risk factors) • Double-blind, placebo-controlled • 7,000 patients • Primary Endpoint • cardiovascular death, non-fatal • myocardial infarction and stroke • Known or recently diagnosed • type 2 diabetes • Acute coronary syndrome • 2-6 weeks prior to randomisation • Excludes • Class II-IV heart failure • eGFR < 45 mL/min/1.73m2

  43. The Atherogenic Lipid Profile Low HDL (small dense) CE Remnant Atheroma CE Small, denseHDL Small, dense LDL Small, dense LDL CE-rich remnants CE Mixed lipaemia as in Metabolic Syndrome,Type 2 diabetes, Familial Combined Hyperlipidaemia, Renal impairment Dysbetalipoproteinaemia

  44. High LDL-C and low HDL-C Are Associated With Increased CHD Risk Framingham Study: Lipids and CHD Risk Intensive LDL and HDL HDL (mg/dL) LDL (mg/dL) Adapted from Am J Med 1977;62:707-714

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