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Residual risk: Is LDL target enough?. An interpretation of the continuous relationship between LDL-C and CVD Therefore, many men and most women with heart.

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Presentation on theme: "Residual risk: Is LDL target enough?. An interpretation of the continuous relationship between LDL-C and CVD Therefore, many men and most women with heart."— Presentation transcript:

1 Residual risk: Is LDL target enough?

2 An interpretation of the continuous relationship between LDL-C and CVD 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. That there is no cut-off cholesterol number below which coronary heart disease cannot develop. Edward F Gibbons MD Editor of New England Journal Medicine Heart Watch June 2001 Vol 5 #5 p3

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

4 Trial WOSCOPAFCAPS/ TexCAPS HPSASPEN CARDS 4SLIPIDCARETNT Total TNT Met S TNT Diabetes N  LDL-C -26%-27%-29% -40%-36%-25%-28%-21%-24%-20% 75% 62% 90% 73% 62% 70% “Residual risk”: Percentage of Major CV Events in Patients on Therapy in statin trials 63% 82% 72% 80% Primary High Diabetics Secondary Aggressive LDL Lowering Risk (<1.8mmol/L -70 mg/dl) The days of the statin “knee-jerk” are numbered

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

6 HDL-C & TG remain predictive of CVD events even when LDL-C < 1.8 mmol/L: TNT & PROVE-IT Barter P et al. NEJM 357: , 2007 On-Treatment Quintile of HDL-C In Pts with LDL-C < 1.8 mmol/L 5 Yr Risk of Major CV Events (%) Q1 Q2 Q3 Q4 Q5 ( 50) Hazard Ratio vs Q1 Q20.85 Q30.57 Q40.55 Q % ≥2.3 mM/L (n=603) < 2.3 mM/L (n=2796) On-Treatment TG In Pts with LDL-C < 1.8 mmol/L day risk of death, MI or recurrent ACS (%) RR 1.56 ( ) p= % Miller et al. 2008

7 CV = cardiovascular Adapted from Stamler J et al Diabetes Care 1993;16: CV mortality per 10,000 person-years Diabetes No diabetes Total cholesterol (mmol/L) <4.74.7–5.15.2–5.75.8–6.26.3–6.76.8–7.2> Relationship between cholesterol and CVD mortality with and without diabetes Statin (LIPID, HPS, CARDS) ? Fibrate (FIELD) FIELD200 5 ? HDLc, TG

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

9  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 3 1 Plasma Artery wall 2 How elevated triglyceride levels may damage the arterial wall

10 PROspective CArdiovascular Munster Study (PROCAM): Hypertriglycaeridemia Events/1000 in 8 years Assman, G et al., Am J Cardiol 1992;70: (157/3593) (84/903) (14/106) TG (mmol/l) < > (3/37) An Independent Risk Factor For CAD

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

12 9 cis retinoic acid RXR Fenofibrate: PPAR α transcriptional activation - raises HDLc and lowers TG PPAR Response Element PPAR  ligand Endogenous or synthetic Promoter Target Gene DNA Brown, Plutzky, Circulation, 2007 PPAR  PPAR  -RXR complex

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

14 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 > % BIP (Bezafibrate) -7.3% (0.24) TG > 200 mg/dl -39.5% FIELD (Fenofibrate) -11% (0.16) TG > 204 mg/dl HDL-C < 42 mg/dl -27% ACCORD (Fenofibrate) -8% (0.32) TG > 204 mg/dl HDL-C < 34 mg/dl -31%

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

16 McKenney J. Arch Intern Med 2004;164: Grundy SM, et al. Arch Intern Med 2002;162: Brown BG. Am J Coll Cardiol 2007;99(suppl)6:32C-34C. 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 Chesney C et al. Am Heart J. 2000; Kuvin J et al. Am J Cardiol 2006;98:

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

18 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? Months of follow-up No. at risk ConventionalIntensive Hazard ratio 0.47 (0.24 to 0.73); p=0.007 Conventional Intensive Gæde P et al. N Engl J Med 2003;348: Probability for Primary Composite End Point

19 Prevention of High-Risk and Recurrent Vascular Disease in 2012? Primary Secondary Fish/fish oils?1B1A Fenofibrate1A**1A** Statin1A1A Aspirinsmall1A ACE-I/ARB1A1A Beta-blocker1A*1A Clopidogrelsmall1B ** In dyslipidaemic subjects* in hypertension

20 Darapladib (opposite genetic paradigm)

21 Summary and link to cases

22 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/m 2, 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%

23 Questions concerning Mrs M. L. Which aspect of her risk factor profile is of the greatest concern? A) BP and ACRB) Weight and BMIC) Total and LDL-C D) TG and HDL-CE) Plasma glucose and HbA1C Which aspect of her risk factor profile is most amenable to intervention? A) BP and ACRB) Weight and BMIC) Total and LDL-C D) TG and HDL-CE) 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 BlockerB) Add Ezetimibe C) Add a Calcium Channel BlockerD) Add a sulphonylurea E) Add fenofibrate

24 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/m 2, 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 ACRB) Weight and BMIC) Total and LDL-C D) TG and HDL-CE) Plasma glucose and Hb A1C Which aspect of her risk factor profile is most amenable to intervention? A) BP and ACRB) Weight and BMIC) Total and LDL-C D) TG and HDL-CE) 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 BlockerB) Add Ezetimibe C) Add a Calcium Channel BlockerD) Add a sulphonylurea E) Add fenofibrate

25 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

26 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 METABOLICSYNDROME Hypercoagulability, impaired fibrinolysis Hypoandrogenism (men), Hyperandrogenism (women) Endothelial dysfunction Hyperuricemia Adipose hormones Inflammation Abdominal obesity/ Ectopic fat deposition Insulin resistance/ Hyperinsulinemia Overweight DiabetesCVD Dyslipidemia Low HDL, high TG High ApoB, low Apo A Small dense LDL Elevated fasting or 2-h post-load glycemia

27 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

28 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?

29 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

30 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 1ry EP (P-value) HHS (Gemfibrozil) -34% (0.02) TG > 200 mg/dl LDL-C/HDL-C > % (p=0.005) BIP (Bezafibrate) -7.3% (0.24) TG > 200 mg/dl -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 (Fenofibrate) -8% (0.32) TG > 204 mg/dl HDL-C < 34 mg/dl -31% (p=0.03)

31 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%.

32 More questions concerning Mrs M. L. Fenofibrate may have contributed towards: A) Weight lossB) Lower BP C) Lower HbA1C Fenofibrate lowers which 1 of the following A) HomocysteineB) Serum CreatinineC) Fibrinogen Fenofibrate also increases which 1 of the following A) LDL particle sizeB) Urinary ACRC) Urate The lipid changes associated with fenofibrate use predict its ability to protect against A) RetinopathyB )Neuropathy C) NephropathyD) Amputation

33 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 lossB) Lower BP C) Lower HbA1C It lowers which 1 of the followingA) HomocysteineB) CreatinineC) Fibrinogen It also increases which 1 of the followingA) LDL particle size B) Urinary ACRC) Urate The lipid changes associated with fenofibrate use predict its ability to protect against A) RetinopathyB )Neuropathy C) NephropathyD) Amputation

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

35 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/ /1 mmHg P=0.001

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

37 Fenofibrate lowers which 1 of the following The case for “C” BiochemInflammationOxidationObesity/dbThrombosis Cystatin CHs-CRPOx LDLAdiponectintPA activity Uric acidVCAM-1Ox PLLeptinPAI 1 NTproBNPICAM-1lmw AGEsresistinD-dimer ANPIL6MPOApo CIII Fibrinogen – 11% AdrenomedIL10LpPLA2Apo EVWF NeopterinIL18HbA1cTissue factor Creatinine + 13% sTNF RcinsulinTF inhibitor HCYS + 40%SAAC peptide Ur ACRTIMP 1

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

39 Fenofibrate also increases which 1 of the following? The case for “A” Lemieux ILemieux I, Laperrière L, Dzavik V, Tremblay G, Bourgeois J, Després JP, Atherosclerosis 2002, 162: Laperrière LDzavik VTremblay GBourgeois JDesprés JPAtherosclerosis 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+/ 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)lipoproteinlipidfenofibrateLDLfenofibrate LDL

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

41 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 TMDavis 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.Ting RBest JDDonoghoe MWDrury PLSullivan DRJenkins AJO'Connell RLWhiting MJGlasziou PPSimes RJKesäniemi YAGebski VJScott RSKeech ACFenofibrate Intervention and Event Lowering in Diabetes Study investigators Diabetologia.Diabetologia. 2011;54: 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)

42 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.

43 Questions concerning Mr G.E. What test would be the most helpful to investigate “residual risk” A) hs-CRP B) Total homocysteineC) Lipoprotein (a) D) Lipoprotein-associated Phospholipase A2E) Urinary ACR Which of the following interventions might help to improve HDL-C? A) Increased activityB) Weight lossC) Cessation of cannabis D) All of the above E) Change from beer to wine consumption

44 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 homocysteineC) Lipoprotein (a) D) Lipoprotein-associated Phospholipase A2E) Urinary ACR Which of the following interventions might help to improve HDL-C? A) Increased activityB) Weight lossC) Cessation of cannabis D) All of the above E) Change from beer to wine consumption

45 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

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

47 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

48 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.

49 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 fibrateB) Add a bile acid resinC) 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-CC) 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

50 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.

51 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 HDL 2 apoA-I HDL 3 Nascent HDL

52 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

53 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%.

54 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

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


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