Diabetic dyslipidemia: The proatherogenic role of CETP and future use of CETP inhibitors Prof. John Betteridge University College London United Kingdom 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 complicationsunless preventive action is taken.” Prof Sir George Alberti, IDF President. International Diabetes Federation Risk of Fatal and Non-fatal CHD in Men with Type 2 Diabetes 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) No diabetes No CHD Diabetes and CHD Diabetes Late onset Early onset Rate 8.7 15.7 21.7 25.7 Nb events 229 36 18 70 HR* 1 1.69 (1.182.41) 2.93 (1.74-4.64) 2.62 (1.99-3.44) HR** 1 1.55 (1.082.21) 2.63 (1.56-4.42) 2.61 (1.96-3.49) *Adjusted on age, smoking, alcohol consumption,social class, BMI, physical activity and previous stroke; ** Further adjustment on risk factors Vannamethee SG et al. Arch Intern Med 2011. Numbers of People (106) with Diabetes for 2000 and 2010 26.5 14.2 32.9 17.5 24% 23% 84.5 132.3 9.4 57% 14.1 15.6 50% 22.5 1.0 44% 1.3 30% 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. Survival Post-MI in Diabetic and Non-diabetic Men and Women Survival (%) 90 80 100 Men (n=1628) 70 60 50 40 Women 90 (n=228) Survival (%) 100 0 80 (n=568) 70 60 50 (n=156) 40 0 0 10 20 304050607080 0 10 20 304050607080 Months post-MI Months post-MI No diabetes Diabetes Sprafka JM et al Diabetes Care 1991;14:537. 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 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 UKPDS: Risk Factors for MI. • • • • • LDL cholesterol HDL cholesterol HbA1c Systolic blood pressure Smoking Baseline Epidemiology Data Turner et al BMJ 1998 Atherogenic Dyslipidaemia ( Metabolic Syndrome, Type 2 Diabetes) Triglycerides Insulin resistance Small, dense LDL Remnants HDL2 Clinical Manifestations of Central Obesity Type 2 diabetes dysglycaemia Insulin resistance FFAs Adiponectin Central Obesity Dyslipidaemia low HDL small, dense LDL hypertriglyceridaemia Hypertension Endothelial dysfunction Inflammation (hsCRP) Impaired thrombolysis PAI-1 Courtesy of Selwyn AP, Weissman PN. Lipoprotein Metabolism in Insulin Resistance and Type 2 Diabetes Adipose tissue LDL profile by electrophoresis ADIPONECTIN NEFA VLDL Normal LDL Lipoprotein lipase Elevated TRL Chylomicrons Intestine 4 2 0 TG CE Pattern A CE CETP TG TG-rich LDL TG CE Plasma Triglycerides (mmol/l) Small, dense LDL diabetes Type 2 Controls 0 2 4 6 9 12 24 Hours Hepatic lipase Pattern B Characteristics of LDL Subclasses Large, buoyant LDL Small, dense LDL pattern A Phospholipids pattern B GAG-binding segments (3147–3157) (3359–3367) 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 The Absolute Concentration of LDL-C Can be Misleading in Subjects with Small, Dense LDL. Large, buoyant particles Apo B Small, dense particles More apo B Sniderman AD et al Ann Intern Med 2001 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 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 Statins:The Evidence Base. Placebo MI rate per 100 subjects per 5 years Continuum of risk 22.6 Secondary prevention 12.9 HPS 2.8 CARE (pravastatin) LIPID (pravastatin) 8.44 7.9 4S (simvastatin) High-risk CHD patients (high cholesterol) Primary prevention WOSCOPS (pravastatin) AFCAPS/TexCAPS (lovastatin) Majority of CHD patients (broad range of cholesterol levels) Patients at high risk of CHD (high cholesterol) Patients at low risk of CHD (low HDL-C) 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 2,838 Patients d/b PBO 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. Median Lipid Levels by Treatment Total cholesterol (mmol/L) LDL cholesterol (mmol/L) Average difference 26% Average difference 40% 1.40 mmol/L (54mg/dL) p<0.0001 1.20 mmol/L (46mg/dL) p<0.0001 6 4 3 4 2 2 1 0 0 0 1 2 3 4 4.5 0 Years of Study Placebo 1 2 3 Years of Study Atorvastatin 4 4.5 Median Lipid Levels by Treatment HDL cholesterol (mmol/L) Triglycerides (mmol/L) Average difference 1% Average difference 19% 0.02 mmol/L,0.8mg/dL p=0.0002 0.39 mmol/L, 35mg/dL p<0.0001 1.4 2 1.2 1 .8 1 .6 .4 .2 0 0 0 1 2 3 4 4.5 0 Years of Study Placebo 1 2 3 Years of Study Atorvastatin 4 4.5 Cumulative Hazard for Primary Endpoint Cumulative Hazard (%) 15 Relative Risk -37% (95% CI: -52, -17) Placebo 127 events P=0.001 2.46/100 person yrs 10 Atorvastatin 83 events 1.54/100 person yrs 5 0 0 Number at risk Placebo 1410 1 2 3 4 4.75 1351 1306 651 305 Atorva 1022 1392 1361 1074 694 328 1428 Years Incidence of major vascular events (%) Heart Protection Study Diabetes Subgroups With/Without CHD or Other CVD 50 Placebo Simvastatin 40 mg 40 RRR 12% RRR 22% 30 RRR 23% 20 RRR 19% RRR 31% 10 1009 0 972 Diabetes + CHD 5683 5722 No diabetes + CHD 519 551 Diabetes + other CVD 1481 1449 1455 1457 No diabetes + other CVD Diabetes + no CVD HPS Collaborative Group. Lancet. 2003;361:2005 LDL-C and change in percent atheroma volume in IVUS studies 2 REVERSAL5 1.5 pravastatin CAMELOT4 placebo Change in Percent Atheroma Volume* (%) 1 ACTIVATE1 placebo 0.5 50 60 70 80 90 Mean LDL-C (mg/dL) -0.5 Progression placebo atorvastatin 0 -1 A-Plus2 REVERSAL5 100 110 120 Regression ASTEROID3 rosuvastatin †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 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. Atherogenic Dyslipidaemia ( Metabolic Syndrome, Type 2 Diabetes) Triglycerides Insulin resistance Small, dense LDL Remnants HDL2 HPS Diabetic Cohort Benefits of Simvastatin by Baseline LDL and HDL-Cholesterol 35 27.9 30 25 20 31.1 23.3 20.9 25.9 21.3 15.7 16.8 15 10 5 0 2nd Qtr 3rd Qtr 4th Qtr LDL-Cholesterol HDL-Cholesterol 3mmol 3mmol 0.9mmol 0.9mmol 1st Qtr Placebo West Simvastatin North Role of Cholesteryl Ester Transfer Protein (CETP) in Lipoprotein Metabolism HDL2 VLDL Enrichment with cholesteryl esters CE CETP TG Transient enrichment with triglycerides (TG) HL Hepatic Lipase (HL) small dense LDL Formation of small dense LDL Facilitated modification of LDL Formation of small HDL3 and lipid-poor pre-HDL HDL3 Pre HDL Regeneration of HDL or removal from circulation, e.g. by renal filtration Von Eckardstein, Expert Review of Cardiovascular Therapy 2010, 8(3):345–58. Dysfunctional HDL in Diabetes A-I CE CE TG TG A-I Oxidation CETP↑ Glu A-I A-I CE TG PAF-AH Glx J A-I PAF-AH A-I PAF-AH SAA • 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 reendothelialisation↓ 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. Circulation 2010, 121:110–122. 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 eg torcetrapib, (ILLUMINATE), dalcetrapib, anacetrapib ILLUMINATE: Recent Post Hoc Analysis: • 6661 patients with DM: in torcetrapib/atorvastatin arm vs. atorvastatin arm – – – – significant significant significant significant lower plasma glucose levels: 0.34 mmol/L lower HbA1c levels: 0.1% vs. 0.3% increase lower insulin levels: 11.7 µU/ml lower HOMA: increase in atorvastatin arm Mechanism? Barter et al, Circulation 2011; 124: 555–562. “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 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 eg torcetrapib, (ILLUMINATE), dalcetrapib, anacetrapib 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 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 eg torcetrapib, (ILLUMINATE), dalcetrapib, anacetrapib Long term Effects of Pioglitazone on HDL-Cholesterol and Triglycerides in CVD Trials 20.0% 10.0% 0.0% Triglycerides HDL-Chol -10.0% -20.0% PROACTIVE CHICAGO PERISCOPE Dormandy et al Lancet, 2005; 366: 1279 Mazzone T et al. JAMA, 2006; 296: 2572 Nissen et al JAMA, 2008; 299: 1562 Intravascular Ultrasound of Coronary Arteries Determining the Atheroma Area Precise planimetry of EEM and lumen borders allows calculation of atheroma cross-sectional area EEM Area Lumen onlyArea parameter On multivariate analysis the 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 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 Plaque echo lucency using carotid ultrasound with integrated back scatter Pre Treatment Post Treatment for 1 month with Pioglitazone Aleglitazar Balanced Activation of PPAR- and - Fold activation of PPAR- Fold activation of PPAR- 32 24 16 8 0 –11 –10 –9 –8 ↑ –7 –6 –5 –4 Roche data on file. Henry et al. Lancet 2009; 374:126. 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. The SYNCHRONY Study Effects of Aleglitazar on Lipids and Lipoproteins Trigs HDL-Chol LDL-Chol Apo B Henry et al. Lancet 2009; 374:126. 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 Hypertension ↓ HbA1c 0.85% ↓ FPG –2.16 mmol/L ↓ HOMA-IR 35% ↓ Blood pressure 1 to 3 mmHg Henry et al. Lancet 2009; 374:126. Aleglitazar Ongoing Trial – ALECARDIO Screened Patients Index ACS Event Run-in Period 2–6 weeks Treatment Period (until 950 events) at least 2.5 years Aleglitazar 150 µg Placebo 4 weeks Follow-up Standard of care (diabetes and other CV risk factors) Known or recently diagnosed Double-blind, placebo-controlled type 2 diabetes Acute coronary syndrome 7,000 patients 2-6 weeks prior to randomisation Primary Endpoint Excludes cardiovascular death, non-fatal Class II-IV heart failure myocardial infarction and stroke eGFR < 45 mL/min/1.73m2 The Atherogenic Lipid Profile Low HDL (small dense) CE Remnant CE Small, dense HDL Small, dense LDL Atheroma Small, CE-rich dense LDL remnants Mixed lipaemia as in Metabolic Syndrome,Type 2 diabetes, Familial Combined Hyperlipidaemia, Renal impairment Dysbetalipoproteinaemia CE High LDL-C and low HDL-C Are Associated With Increased CHD Risk Framingham Study: Lipids and CHD Risk C 3.0 H D 2.0 R I 1.0 S K 0.0 100 220 160 85 65 45 25 HDL (mg/dL) LDL (mg/dL) Adapted from Am J Med 1977;62:707-714