Residual risk: Is LDL target enough?

An interpretation of the continuous relationship between LDL-C and CVD That there is no cut-off cholesterol number below which coronary heart disease cannot develop. Therefore, many men and most women with heart disease have lipid problems other than high total or LDL cholesterol that put them at risk for heart disease. Edward F Gibbons MD Editor of New England Journal Medicine Heart Watch June 2001 Vol 5 #5 p3

High Cholesterol + Simvastatin Neovascularisation of vasa vasorum in unstable leisions: A source of plaque? Normal High Cholesterol High Cholesterol + Simvastatin

“Residual risk”: Percentage of Major CV Events in Patients on Therapy in statin trials 90% 82% 72% 80% 73% 75% 75% 70% 62% 63% 62% Primary High Diabetics Secondary Aggressive LDL Lowering Risk (<1.8mmol/L -70 mg/dl) The days of the statin “knee-jerk” are numbered Trial WOSCOP AFCAPS/ TexCAPS HPS ASPEN CARDS 4S LIPID CARE TNT Total Met S Diabetes N 6.595 6.505 20.536 2.410 2.838 4.444 9.014 4.159 10.001 5.584 1.501 LDL-C -26% -27% -29% -40% -36% -25% -28% -21% -24% -20%

Residual risk on statin treatment in diabetes remains high (control Diabetic CVD rate set to = 100%) 62% 78% 77% 64% 89% Non-db risk

HDL-C & TG remain predictive of CVD events even when LDL-C < 1 HDL-C & TG remain predictive of CVD events even when LDL-C < 1.8 mmol/L: TNT & PROVE-IT 5 Yr Risk of Major CV Events (%) Hazard Ratio vs Q1 Q2 0.85 Q3 0.57 Q4 0.55 Q5 0.61 12 10 8 6 4 2 Q1 Q2 Q3 Q4 Q5 (<38) (38<42) (42<46) (46<50) (>50) RR 1.56 (1.28-1.89) p= 0.001 20.3 +64% +56% 13.5 30-day risk of death, MI or recurrent ACS (%) ≥2.3 mM/L (n=603) < 2.3 mM/L (n=2796) On-Treatment Quintile of HDL-C In Pts with LDL-C < 1.8 mmol/L On-Treatment TG In Pts with LDL-C < 1.8 mmol/L Barter P et al. NEJM 357:1301-10, 2007 Miller et al. 2008

CV mortality per 10,000 person-years Total cholesterol (mmol/L) Relationship between cholesterol and CVD mortality with and without diabetes 160 Diabetes No diabetes 140 Statin (LIPID, HPS, CARDS) 120 100 CV mortality per 10,000 person-years 80 ? Fibrate (FIELD) 60 ? HDLc, TG 40 20 <4.7 4.7–5.1 5.2–5.7 5.8–6.2 6.3–6.7 6.8–7.2 >7.3 Total cholesterol (mmol/L) CV = cardiovascular Adapted from Stamler J et al Diabetes Care 1993;16:434-444. FIELD2005

Dyslipidaemias Secondary to Hypertriglyceridaemia Hepatic lipase Bloodstream CETP LDL Small, dense LDL CETP Increased VLDL Rapid renal filtration of apo A-I HDL Small, dense HDL Hepatic lipase Liver Increased triglycerides 8

How elevated triglyceride levels may damage the arterial wall TG (> 1.5 mmol/l ?) drives cholesterol ester transfer via CETP : 1) TG exchange reduces HDL-C and impairs reverse cholesterol transport. TG and HDL-C levels are inversely correlated 2) TG exchange causes (pro-atherogenic) smaller, denser LDL. When TG is raised, LDL-C underestimates CVD risk. 3) Small, rather than large, TG-rich particles may carry cholesterol into the artery wall. The linear relationship between TG and CVD risk declines at very high levels 2 3 1 Plasma Artery wall

PROspective CArdiovascular Munster Study (PROCAM): Hypertriglycaeridemia An Independent Risk Factor For CAD 140 120 100 Events/1000 in 8 years 80 60 40 44 93 132 81 20 TG (mmol/l) <2.3 2.3-4.5 4.5-9.0 >9.0 (157/3593) (84/903) (14/106) (3/37) Assman, G et al., Am J Cardiol 1992;70:733-737

Dyslipidaemia (low HDL-C, high TG) is prevalent amongst high risk groups CCU: > 40% high TG, > 50% low HDLc ASPAC MI: 47% HDL-c < 1.0mM, 52% TG > 1.7mM T2DM: ~ 50% high TG, ~ 60% low HDLc

Fenofibrate: PPAR α transcriptional activation - raises HDLc and lowers TG PPAR ligand Endogenous or synthetic PPAR  9 cis retinoic acid RXR Target Gene PPAR-RXR complex DNA Promoter PPAR Response Element Brown, Plutzky, Circulation, 2007

Fibrates regulate lipid metabolism… Liver Circulation Results apo A-I … by controlling the expression of PPAR target genes Increased HDL Production apo A-II HDL ABCA1 ABCG1 Decreased VLDL Production VLDL apo C-III Apo A-V Increased VLDL Clearance TG FFA Decreased TG levels Acyl-CoA Synthase LPL Reversal of CETP formation of small and dense LDL particles LDL Acetyl CoA Duval C, et al. Trends Mol Med. 2002;8:422-430. Lee CH, et al. Endocrinology. 2003;144:2201-2207.

Comparison of ACCORD and FIELD subgroup results with those from prior fibrate studies Trial (Drug) Primary Endpoint: Entire Cohort (P-value) Lipid Subgroup Criterion Pre-specified Endpoint: Subgroup HHS (Gemfibrozil) -34% (0.02) TG > 200 mg/dl LDL-C/HDL-C > 5.0 -71% BIP (Bezafibrate) -7.3% (0.24) -39.5% FIELD (Fenofibrate) -11% (0.16) TG > 204 mg/dl HDL-C < 42 mg/dl -27% ACCORD -8% (0.32) HDL-C < 34 mg/dl -31%

A working hypothesis for niacin mechanism of action GPR109A 3: Hepatic lipase O N HDL↑ CETP CE VLDL ↓ TG [cAMP]i↓ TG FFA VLDL-TG Adipocyte FFA↓ 1: Inhibits hormone sensitive lipase TG Liver 2: Inhibits DGAT 2 15

Niacin: Efficacy includes LDL-C reduction In patients with diabetes and mixed dyslipidaemia, Niacin has been shown to Increase HDL-C levels 15%-30% Decrease TG levels 15%-50% Have dose-dependent effects on LDL-C levels (up to 40%) Decrease lipoprotein(a) levels by 25% Decrease fibrinogen levels by 14% Decrease Lp-PLA2 by an additional 20% when added to statin therapy McKenney J. Arch Intern Med 2004;164:697-705. Grundy SM, et al. Arch Intern Med 2002;162:1568-1576. Brown BG. Am J Coll Cardiol 2007;99(suppl)6:32C-34C. Chesney C et al. Am Heart J. 2000;140-631-6. Kuvin J et al. Am J Cardiol 2006;98:743-745.

Steno 2: Multifactorial Intensive Intervention in Type 2 Diabetes Percent of Patients Achieving Targets Intensive Conventional 100 P<0.001 P=0.21 80 P=0.19 P<0.001 Patients (%) 60 40 P=0.06 20 HbA1c <6.5% TG<1.80 mmol/L SBP<130 mm Hg DBP<80 mm Hg Chol <4.5 mmol/L Gaede et al. N Engl J Med 2003;348:383–393

Steno 2 CVD endpoints. 85 CVD events in 35 conventional patients (44%) versus 33 CVD events in 19 intensive patients (24%) FIELD event rate: No longer ”coronary equivalent”, or only if prolonged? 0.6 Conventional 0.5 0.4 Probability for Primary Composite End Point 0.3 Intensive 0.2 0.1 Hazard ratio 0.47 (0.24 to 0.73); p=0.007 0.0 12 24 36 48 60 72 84 96 Months of follow-up Conventional Intensive 80 72 78 70 74 63 71 59 66 50 63 44 61 41 59 13 19 No. at risk Gæde P et al. N Engl J Med 2003;348:383-93

Prevention of High-Risk and Recurrent Vascular Disease in 2012? Primary Secondary Fish/fish oils ?1B 1A Fenofibrate 1A** 1A** Statin 1A 1A Aspirin small 1A ACE-I/ARB 1A 1A Beta-blocker 1A* 1A Clopidogrel small 1B * in hypertension ** In dyslipidaemic subjects

Darapladib (opposite genetic paradigm)

Summary and link to cases

Mrs M. L. This 56 year-old lady, who recently suffered a TIA, has a history of SVT, type 2 diabetes diagnosed 4 years ago, and hypertension treated from that point in time. Drug treatment includes Metformin 500 mg x 2 BD, Aspirin 100mg, enalapril 10 mg BD, indapamide 2.5 mg, atenolol 50 mg and maximal tolerated statin dose (simvastatin 40 mg) Her weight is 68 kg, BMI 28 kg/m2, BP 155/98 mmHg Total cholesterol 5.4 mmol/l, fasting TG 3.9 mmol/l, HDL 1.1 mmol/l, calculated LDL 2.5 mmol/l. Urinary ACR is 4.2 HbA1C is 7.3%

Questions concerning Mrs M. L. Which aspect of her risk factor profile is of the greatest concern? A) BP and ACR B) Weight and BMI C) Total and LDL-C D) TG and HDL-C E) Plasma glucose and HbA1C Which aspect of her risk factor profile is most amenable to intervention? A) BP and ACR B) Weight and BMI C) Total and LDL-C D) TG and HDL-C E) Plasma glucose and HbA1C If refusal to take more than 1 extra tablet was a limitation, what would you do? A) Add an AII Receptor Blocker B) Add Ezetimibe C) Add a Calcium Channel Blocker D) Add a sulphonylurea E) Add fenofibrate

This 56 year-old lady, who recently suffered a TIA, has history of SVT, type 2 diabetes diagnosed 4 years ago, and hypertension treated from then. Drugs: Metformin 500 mg x 2 BD, Aspirin 100mg, enalapril 10 mg BD, indapamide 2.5 mg, atenolol 50 mg and maximal tolerated statin dose (simvastatin 40 mg) Weight is 68 kg, BMI 28 kg/m2, BP 155/98 mmHg, Total cholesterol 5.4 mmol/l, fasting TG 3.9 mmol/l, HDL 1.1 mmol/l, calculated LDL-C 2.5 mmol/l. Urinary ACR is 4.2 HbA1C is 7.3% Which aspect of her risk factor profile is of the greatest concern? A) BP and ACR B) Weight and BMI C) Total and LDL-C D) TG and HDL-C E) Plasma glucose and Hb A1C Which aspect of her risk factor profile is most amenable to intervention? A) BP and ACR B) Weight and BMI C) Total and LDL-C D) TG and HDL-C E) Plasma glucose and Hb A1C If refusal to take more than 1 extra tablet was a limitation, what would you do? A) Add an AII Receptor Blocker B) Add Ezetimibe C) Add a Calcium Channel Blocker D) Add a sulphonylurea E) Add fenofibrate

Which aspect of her risk factor profile is of the greatest concern? BP and ACR Weight and BMI Total and LDL-C TG and HDL-C Plasma glucose and HbA1C

impaired fibrinolysis Endothelial dysfunction Ectopic fat deposition Which aspect of her risk factor profile is of the greatest concern? The case for “B” overall (others individually) Diet Physical activity/ fitness Socioeconomic status Birth size, childhood growth Genes Hypertension M E T A B O L I C S Y N D R Hypercoagulability, impaired fibrinolysis Hypoandrogenism (men), Hyperandrogenism (women) Endothelial dysfunction Hyperuricemia Adipose hormones Inflammation Abdominal obesity/ Ectopic fat deposition Insulin resistance/ Hyperinsulinemia Overweight Diabetes CVD Dyslipidemia Low HDL, high TG High ApoB, low Apo A Small dense LDL Elevated fasting or 2-h post-load glycemia

Which aspect of her risk factor profile is most amenable to intervention? A) BP and ACR B) Weight and BMI C) Total and LDL-C D) TG and HDL-C E) Plasma glucose and Hb A1C

Which aspect of her risk factor profile is most amenable to intervention? The case for “D”  The three specific primary ACCORD hypotheses were as follow. In middle-aged or older people with type 2 diabetes who are at high risk for having a cardiovascular disease (CVD) event because of existing clinical or subclinical CVD or CVD risk factors: does a therapeutic strategy that targets a HbA1c of < 6.0% reduce the rate of CVD events more than a strategy that targets a HbA1c of 7.0% to 7.9% (with the expectation of achieving a median level of 7.5%) ? in the context of good glycaemic control, does a therapeutic strategy that uses a fibrate to raise HDL-C/lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C? In the context of good glycaemic control, does a therapeutic strategy that targets a systolic blood pressure (SBP) < 120 mm Hg reduce the rate of CVD events compared to a strategy that targets a SBP of < 140 mm Hg?

If refusal to take more than 1 extra tablet was a limitation, what would you do? Add an AII Receptor Blocker B) Add Ezetimibe C) Add a Calcium Channel Blocker D) Add a sulphonylurea E) Add fenofibrate

If refusal to take more than 1 extra tablet was a limitation, what would you do? The case for “E” Trial (Drug) Overall Effect 1ry EP (P-value) Lipid Subgroup Subgroup Effect HHS (Gemfibrozil) -34% (0.02) TG > 200 mg/dl LDL-C/HDL-C > 5.0 -71% (p=0.005) BIP (Bezafibrate) -7.3% (0.24) -39.5% (p<0.01) VA-HIT (Gemfibrozil) -22% (0.006) Diabetes -32% (p=0.004) FIELD (Fenofibrate) -11% (0.16) TG > 204 mg/dl HDL-C < 42 mg/dl -27% (p=0.005) (31%*; 0.002*) ACCORD -8% (0.32) HDL-C < 34 mg/dl -31% (p=0.03)

Mrs M. L. You cheat. You replace her Enalapril and Indapamide with a higher dose combination agent and replace her simvastatin with a tolerable dose of the atorvastatin felodipine combination. (or change her metformin 500 mg ii bd to I g bd or Metformin XR daily) Having done so, this leaves room to add Fenofibrate 145 mg/day. Repeat results reveal : weight is 65 kg (3kg decrease), BP 125/85, Total cholesterol 4.4 mmol/l, fasting TG 1.9 mmol/l, HDL 1.4 mmol/l, calculated LDL 2.1 mmol/l. Urinary ACR is 3.2 and HbA1C is 7.1%.

More questions concerning Mrs M. L. Fenofibrate may have contributed towards: A) Weight loss B) Lower BP C) Lower HbA1C Fenofibrate lowers which 1 of the following A) Homocysteine B) Serum Creatinine C) Fibrinogen Fenofibrate also increases which 1 of the following A) LDL particle size B) Urinary ACR C) Urate The lipid changes associated with fenofibrate use predict its ability to protect against A) Retinopathy B )Neuropathy C) Nephropathy D) Amputation

You cheat. You replace her Enalapril and Indapamide with a higher dose combination agent and repalce her simvastatin with a tolerable dose of the atorvastatin felodipine combination. Having done so, this leaves room to add Fenofibrate 145 mg/day. Repeat results reveal : weight is 65 kg (3kg decrease), BP 125/85, Total cholesterol 4.4 mmol/l, fasting TG 1.9 mmol/l, HDL 1.4 mmol/l, calculated LDL 2.1 mmol/l. Urinary ACR is 3.2 and HbA1C is 7.1%. Fenofibrate may have contributed towards: A) Weight loss B) Lower BP C) Lower HbA1C It lowers which 1 of the following A) Homocysteine B) Creatinine C) Fibrinogen It also increases which 1 of the following A) LDL particle size B) Urinary ACR C) Urate The lipid changes associated with fenofibrate use predict its ability to protect against A) Retinopathy B )Neuropathy C) Nephropathy D) Amputation

Fenofibrate may have contributed towards: A) Weight loss B) Lower BP C) Lower HbA1C

Fenofibrate may have contributed towards: The case for “B” BP (mm Hg) Plac Feno Weight (kg) Plac Feno Study entry Study end 140/82 140/82 138/78 136/77 86 86 - 2 /1 mmHg P=0.001

Fenofibrate lowers which 1 of the following A) Homocysteine B) Serum Creatinine C) Fibrinogen

Fenofibrate lowers which 1 of the following The case for “C” Biochem Inflammation Oxidation Obesity/db Thrombosis Cystatin C Hs-CRP Ox LDL Adiponectin tPA activity Uric acid VCAM-1 Ox PL Leptin PAI 1 NTproBNP ICAM-1 lmw AGEs resistin D-dimer ANP IL6 MPO Apo CIII Fibrinogen – 11% Adrenomed IL10 LpPLA2 Apo E VWF Neopterin IL18 HbA1c Tissue factor Creatinine + 13% sTNF Rc insulin TF inhibitor HCYS + 40% SAA C peptide Ur ACR TIMP 1

Fenofibrate also increases which 1 of the following A) LDL particle size B) Urinary ACR C) Urate

Fenofibrate also increases which 1 of the following? The case for “A” Lemieux I, Laperrière L, Dzavik V, Tremblay G, Bourgeois J, Després JP, Atherosclerosis 2002, 162:363-371 RESULTS: Whereas significant improvements in the plasma lipoprotein-lipid variables were observed with both fenofibrate and pravastatin treatments, LDL peak particle size was only significantly increased withfenofibrate therapy (+2.11+/-5.18 A, P<0.05). Among patients under fenofibrate therapy, changes in TG levels were negatively associated with changes in LDL peak particle size (r=-0.54, P<0.0007)

The lipid changes associated with fenofibrate use predict its ability to protect against A) Retinopathy B) Neuropathy C) Nephropathy D) Amputation

The lipid changes associated with fenofibrate use predict its ability to protect against? The case for “ C” Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, Jenkins AJ, O'Connell RL, Whiting MJ, Glasziou PP, Simes RJ, Kesäniemi YA,Gebski VJ, Scott RS, Keech AC; Fenofibrate Intervention and Event Lowering in Diabetes Study investigators. Diabetologia. 2011;54:280-90. Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs. 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs. 520 without) and reductions of ≥ 0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs. 303 without)

Mr G.E. This non-diabetic 49 year - old male was a smoker until he required CABG at age 43. Despite treatment with aspirin 100mg and Vytorin 40/10mg he required stenting recently. Hypercholesterolaemia persists at a level of 5.2 mmol/l (fasting TG 1.1 mmol/l, HDL 0.9 mmol/l, calculated LDL 3.8 mmol/l). He had resumed occasional use of cannabis.

Questions concerning Mr G.E. What test would be the most helpful to investigate “residual risk” A) hs-CRP B) Total homocysteine C) Lipoprotein (a) D) Lipoprotein-associated Phospholipase A2 E) Urinary ACR Which of the following interventions might help to improve HDL-C? A) Increased activity B) Weight loss C) Cessation of cannabis D) All of the above E) Change from beer to wine consumption

This non-diabetic 49 year - old male was a smoker until he required CABG at age 43. Despite treatment with aspirin 100mg and Vytorin 40/10mg he required stenting recently. Hypercholesterolaemia persists at a level of 5.2 mmol/l (fasting TG 1.1 mmol/l, HDL 0.9 mmol/l, calculated LDL 3.8 mmol/l). He had resumed occasional use of cannabis. What test would be the most helpful to investigate “residual risk” A) hs-CRP B) Total homocysteine C) Lipoprotein (a) D) Lipoprotein-associated Phospholipase A2 E) Urinary ACR Which of the following interventions might help to improve HDL-C? A) Increased activity B) Weight loss C) Cessation of cannabis D) All of the above E) Change from beer to wine consumption

What test would be the most helpful to investigate “residual risk” A) hs-CRP B) Total homocysteine C) Lipoprotein (a) D) Lipoprotein-associated Phospholipase A2 E) Urinary ACR

What test would be the most helpful to investigate “residual risk” The case for “C” Emerging Risk Factor Collaboration. JAMA 2009; 302: 412-23

Which of the following interventions might help to improve HDL-C? A) Increased activity B) Weight loss C) Cessation of cannabis D) All of the above E) Change from beer to wine consumption

Which of the following interventions might help to improve HDL-C Which of the following interventions might help to improve HDL-C? The case for “C”, but “D” rarely considered The mean triglyceride level in the 18 marijuana users was 1.5 mmol/l, compared with 1.0 mmol/l in the 24 controls. This is consistent with a previous paper that reported significant increases in HDL-triglyceride concentrations in marijuana users compared with controls. Jayanthi S, Buie S, Moore S, et al. Heavy marijuana users show increased serum apolipoprotein C3 levels: evidence from proteomic analyses. Mol Psychiatry 2008.

More questions concerning Mr G.E. Mr G.E’s Lipoprotein (a) level was very high (1,783 mg/l). With this in mind, how would you intensify lipid management? A) Add a fibrate B) Add a bile acid resin C) Increase Vytorin (to 80/10mg) D) Replace Vytorin with Rosuvastatin plus Ezetimibe E) Add Niacin 1 to 2 gm / day, as tolerated. How much improvement do you anticipate? A) 50% decrease in TG B) 30% increase in HDL-C C) 25% decrease in Lp(a) D) 30% decrease in LDL-C E) All of the above Niacin affects plasma glucose because A) It affects pancreatic beta cell function B) It increases plasma free fatty acid levels C) It reduces plasma free fatty acid levels which then re-bound D) It increases the speed of intestinal absorption. E) The mechanism is unknown

How would you intensify lipid management? A) Add a fibrate B) Add a bile acid resin C) Increase Vytorin (to 80/10mg) D) Replace Vytorin with Rosuvastatin plus Ezetimibe E) Add Niacin 1 to 2 gm / day, as tolerated.

How would you intensify lipid management? The case for “E” Hepatocyte Inhibits hepatic lipase activity which reduces lipolysis of large HDL No effect on increasing Apo A1 synthesis A-I CE HDL2 apoA-I HDL3 Nascent HDL

How much improvement do you anticipate? A) 50% decrease in TG B) 30% increase in HDL-C C) 25% decrease in Lp(a) D) 30% decrease in LDL-C E) All of the above

How much improvement do you anticipate? The case for “E” Niacin used at pharmacologic doses (2 g/d) has been shown to reduce serum levels of Lp(a) by 20% to 25%.

Niacin affects plasma glucose because... A) It affects pancreatic beta cell function B) It increases plasma free fatty acid levels C) It reduces plasma free fatty acid levels which then re-bound D) It increases the speed of intestinal absorption. E) The mechanism is unknown

Niacin affects plasma glucose because... The case for “C”