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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

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 70% 62% 73% 90% 63% 62% 75% 75% 80% 72% 82% Primary High Diabetics Secondary Aggressive LDL Lowering Risk (<1.8mmol/L -70 mg/dl) Trial WOSCOP AFCAPS/ TexCAPS HPS N



LDL-C

6.595

-26% 6.505

-27%

The days of the statin “knee-jerk” are numbered

20.536

-29%

ASPEN CARDS

2.410

-29% 2.838

-40%

4.444

-36%

LIPID

9.014

-25%

CARE

4.159

-28%

TNT Total

10.00

1 -21%

TNT Met S

5.584

-24%

TNT Diabetes

1.501

-20%

Residual risk on statin treatment in diabetes remains high

(control Diabetic CVD rate set to = 100%)

62% 78% 77% 64% 89%

statin Non db risk

6 4 2 0 HDL-C & TG remain predictive of CVD events even when LDL-C < 1.8 mmol/L: TNT & PROVE-IT 12 10 8 Hazard Ratio vs Q1 Q2 0.85

Q3 Q4 Q5 0.57

0.55

0.61

+64% 20.3

RR 1.56 (1.28-1.89) p= 0.001

13.5

+56 % Q1 Q2 Q3 Q4 Q5

(<38) (38<42) (42<46) (46<50) (>50)

On-Treatment Quintile of HDL-C In Pts with LDL-C < 1.8 mmol/L

Barter P et al. NEJM 357:1301-10, 2007

≥2.3 mM/L (n=603) < 2.3 mM/L (n=2796) On-Treatment TG In Pts with LDL-C < 1.8 mmol/L

Miller et al. 2008

Relationship between cholesterol and CVD mortality with and without diabetes

160 140 120 100 80 60 40 20 0 Diabetes No diabetes

? HDLc, TG

<4.7

4.7–5.1

5.2–5.7

5.8–6.2

6.3–6.7

6.8–7.2

Total cholesterol (mmol/L) >7.3

CV = cardiovascular Adapted from Stamler J et al

Diabetes Care

1993;16:434-444.

FIELD200 5

Bloodstream

Increased VLDL Dyslipidaemias Secondary to Hypertriglyceridaemia LDL HDL

Hepatic lipase

Small, dense LDL Rapid renal filtration of apo A-I Small, dense HDL

Hepatic lipase

Increased triglycerides

Liver

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.

2 3

– 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

1 Plasma Artery wall

PRO spective CA rdiovascular M unster Study ( PROCAM ): Hypertriglycaeridemia

An Independent Risk Factor For CAD 140 120 100 80 60 40 20 0 TG (mmol/l)

44 93 132

<2.3

2.3-4.5

4.5-9.0

(157/3593) (84/903) (14/106) 81

>9.0

(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



PPAR



-RXR complex DNA

Promoter

PPAR Response Element

Brown, Plutzky, Circulation, 2007

RXR

cis

retinoic acid

Target Gene

Fibrates regulate lipid metabolism

…

Liver Circulation

Results

…

by controlling the expression of PPAR  target genes apo A-I apo A-II ABCA1 ABCG1

FFA

apo C-III Apo A-V

Acyl-CoA Synthase Acetyl CoA

LDL HDL VLDL

LPL Increased HDL Production Decreased VLDL Production Increased VLDL Clearance Decreased TG levels Reversal of CETP formation of small and dense LDL particles

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) HHS

(Gemfibrozil)

Primary Endpoint: Entire Cohort (P-value) Lipid Subgroup Criterion

-34% (0.02) TG > 200 mg/dl LDL-C/HDL-C > 5.0

Pre-specified Endpoint: Subgroup

-71%

BIP

(Bezafibrate)

FIELD

(Fenofibrate) -7.3% (0.24) -11% (0.16) TG > 200 mg/dl TG > 204 mg/dl HDL-C < 42 mg/dl -39.5% -27%

ACCORD

(Fenofibrate) -8% (0.32) TG > 204 mg/dl HDL-C < 34 mg/dl -31%

A working hypothesis for niacin mechanism of action

GPR109A O O N TG [cAMP] i ↓ FFA

3: Hepatic lipase

HDL↑ CETP CE VLDL ↓ TG VLDL-TG Adipocyte

1: Inhibits hormone

FFA ↓

sensitive lipase

TG Liver

2: Inhibits DGAT 2

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 100 80 60 40 20 0 P=0.06

Percent of Patients Achieving Targets

Intensive Conventional P<0.001

P=0.19

P<0.001

P=0.21

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%)

0.6

0.5

0.4

0.3

0.2

FIELD event rate: No longer ”coronary equivalent”, or only if prolonged?

Conventional Intensive 0.1

Conventional Intensive No. at risk 0.0

0 80 80 12 72 78 24 70 74 Hazard ratio 0.47 (0.24 to 0.73); p=0.007

72 84 96 36 48 60 Months of follow-up 63 71 59 66 50 63 44 61 41 59 13 19

Gæde P et al. N Engl J Med 2003;348:383-93

• • • • • • •

Prevention of High-Risk and Recurrent Vascular Disease in 2012?

F ish/fish oils Fenofibrate S tatin A spirin A CE-I/ARB B eta-blocker C lopidogrel Primary Secondary ?1B

1A 1A** 1A small 1A 1A** 1A 1A 1A 1A * small 1A 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/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%

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 E) Add fenofibrate D) Add a sulphonylurea

• • • • • • 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 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 D) TG and HDL-C B) Weight and BMI C) Total and LDL-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 E) Add fenofibrate D) Add a sulphonylurea

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 of the greatest concern? The case for “B” overall (others individually) Diet Physical activity/ fitness Socioeconomic status Birth size, childhood growth Genes S Y N D R O M E M E T A B O L I C Inflammation Elevated fasting or 2-h post-load glycemia Overweight Hyperuricemia Dyslipidemia

•

Low HDL, high TG

• High ApoB, low Apo A • Small dense LDL

Abdominal obesity/ Ectopic fat deposition Hypertension Insulin resistance/ Hyperinsulinemia Adipose hormones Endothelial dysfunction Hypercoagulability, impaired fibrinolysis Diabetes CVD Hypoandrogenism

(men)

, Hyperandrogenism

(women)

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?

A) 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 1ry EP (P-value) HHS

(Gemfibrozil)

BIP

(Bezafibrate)

VA-HIT

(Gemfibrozil) -34% (0.02) -7.3% (0.24) -22% (0.006) TG > 200 mg/dl LDL-C/HDL-C > 5.0

TG > 200 mg/dl Diabetes -71% (p=0.005) -39.5% (p<0.01) -32% (p=0.004)

FIELD

(Fenofibrate)

ACCORD

(Fenofibrate) -11% (0.16) -8% (0.32) TG > 204 mg/dl HDL-C < 42 mg/dl -27% (p=0.005) (31%*; 0.002* ) TG > 204 mg/dl 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 • It also increases which 1 of the following A) LDL particle size B) Urinary ACR C) Urate C) Fibrinogen • 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” 30 25 20 15 10 5 0 Lipid lowering * Anti thrombotic ACE inhibitor* ARB β blocker* Ca++ antagonist Digoxin* Nitrate Diuretic* BP (mm Hg) Plac Feno Weight (kg) Plac Feno Study entry Study end 140/82 140/82 138/78 136/77

- 2 /1 mmHg P=0.001

86 86 86 86

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

Cystatin C Uric acid NTproBNP ANP

Inflammation

Hs-CRP VCAM-1 ICAM-1 IL6 Adrenomed Neopterin

Creatinine + 13% HCYS + 40%

Ur ACR IL10 IL18 sTNF Rc SAA TIMP 1

Oxidation

Ox LDL Ox PL lmw AGEs MPO LpPLA2

Obesity/db

Adiponectin Leptin resistin Apo CIII Apo E HbA1c insulin C peptide

Thrombosis

tPA activity PAI 1 D-dimer

Fibrinogen – 11%

VWF Tissue factor TF inhibitor

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 , J , Laperrière L , Dzavik V , Després JP , Atherosclerosis Tremblay G , 2002, 162:363-371 Bourgeois 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 with fenofibrate 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 , RJ , Jenkins AJ , O'Connell RL , Kesäniemi YA , Gebski VJ , Whiting MJ Scott RS , , Glasziou PP Keech AC ; , Simes 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?

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 (to 80/10mg) B) Add a bile acid resin E) Add Niacin 1 to 2 gm / day, as tolerated.

C) Increase Vytorin D) Replace Vytorin with Rosuvastatin plus Ezetimibe • 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

Nascent HDL

apoA-I No effect on increasing Apo A1 synthesis Inhibits hepatic lipase activity which reduces lipolysis of large HDL

HDL 3

CE A-I HDL 2

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