1. Residual risk: Is LDL target enough?

2. 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

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

4. “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%

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

6. 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
Q Q Q Q Q5
(<38) (38<42) (42<46) (46<50) (>50)
RR 1.56 ( )
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: , 2007
Miller et al. 2008

7. 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:
FIELD2005

8. 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

9. 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

10. 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
>9.0
(157/3593) (84/903) (14/106)
(3/37)
Assman, G et al., Am J Cardiol 1992;70:

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 < 1.0mM, 52% TG > 1.7mM
T2DM: ~ 50% high TG, ~ 60% low HDLc

12. 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

13. 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:
Lee CH, et al. Endocrinology. 2003;144:

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 > 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%

15. 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

16. 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:
Grundy SM, et al. Arch Intern Med 2002;162:
Brown BG. Am J Coll Cardiol 2007;99(suppl)6:32C-34C.
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
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

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?
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

19. 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

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/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%

23. 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

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/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

25. 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

26. 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

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?
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
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)

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 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

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 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

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
138/ /77
- 2 /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”
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

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 I, Laperrière L, Dzavik V, Tremblay G, Bourgeois J, Després JP, Atherosclerosis 2002, 162:
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)

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 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:
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 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

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 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

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
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 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

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
HDL2
apoA-I
HDL3
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”