Dyslipidaemia. Is there any new information? Dr. A.R.M. Saifuddin Ekram

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1 Dyslipidaemia Is there any new information? Dr. A.R.M. Saifuddin Ekram PhD,FACP,FCPS(Medicine) Professor(c.c.) & Head Department of Medicine Rajshahi Medical College Rajshahi-6000

2 New features of ATP III Focus on multiple risk factors Modifications of lipid & lipoprotein classification Support for implementation

3 Focus on multiple risk factors 1. Raises persons with DM without CHD (most of whom display multiple risk factors) to the risk level of CHD risk equivalent

4 2. Uses Framingham projections of 10-year absolute CHD risk to identify certain patients with multiple(2+) risk factors for more intensive treatment.

5 3. Identifies persons with multiple metabolic risk factors (metabolic syndrome) as candidate for intensified therapeutic lifestyle changes

6 Modifications of lipid & lipoprotein classification 1. Identifies LDL cholesterol <100 mg/dl as optimal

7 2. Raises categorical low HDL cholesterol from <35 mg/dl to <40 mg/dl because the latter is a better measure of a depressed HDL

8 3. Lowers the triglyceride classification cut-points to give more attention to moderate elevations

9 Support for implementation 1. Recommends lipoprotein analysis (TC,LDL-C,HDL-C & TG ) as preferred initial test, rather than screening for total cholesterol and HDL alone

10 2. Encourages use of plant stanols /sterols and viscous (soluble) fiber as the preferred initial test, rather than screening for total cholesterol and HDL alone

11 3. Presents strategies for promoting adherence to therapeutic lifestyle changes and drug therapies

12 4. Recommends treatment beyond LDL lowering for persons with TG > 200 mg/dl.

13 Target lipid values by level of risk Target values Level of risk LDL-C level, TC:HDL Triglyceride (definition) mmol/l ratio level, mmol/l Very high * (10-year risk of CAD >30%, or history of CV disease or diabetes) <2.5 <4 <2.0 High * (10-year risk 20%-30%) <3.0 <5 <2.0 Moderate (10-year risk 10%-20%) <4.0 <6 <2.0 Low (10-year risk <10%) <5.0 <7 <3.0 *Start medication and lifestyle changes concomitantly if values are above target values. Start medication if target values are not achieved after 3 months of lifestyle modification. Start medication if target values are not achieved after 6 months of lifestyle modification.

14 New Challenges Aging Obesity (> 27 kg/m 2 ) Type 2 DM is at epidemic proportions

15 Focal points Focus on 3 CHD, hard end-point risk levels as used in ATP III Treat to LDL and TC/HDL ratio (and apo B) targets A focus on TC/HDL and apo B ensures that TG problems associated with increased CHD risk will be adequately addressed.

16 Risk Categories Risk category 10-year risk estimate of CVD LDL-C TC:HDL-C ratio apo B High 20% Diabetes Any atherosclerotic disease <2.5 < Moderate 10% - <20% <3.5 < Low < 10% <4.5 <

17 Estimate of 10-Year Risk for Men Age determines first assignment of points Total Cholesterol Age Age Age Age Age < > Nonsmoker Smoker Systolic BP If Untreated If Treated (mmhg) < HDL points are the same for males and females and are not stratified by age

18 Percent with CAD events / 5y The Greater the LDL-C Reduction, the Better the Effect on Coronary Artery Disease Risk 25 4S-P Secondary Prevention S GREACE UC Lipid-P CARE-P CARE HPS-P HPS Lipid WOS-P GREACE WOS AFCAPS AFCAPS-P Primary Prevention mg/dl mmol/l LDL-cholesterol

19 Evidence in 1º Prevention ASCOT: Patient Population Lipid Lowering Arm (LLA) Eligibility criteria SBP 160 mm Hg and/or DBP 100 mm Hg (untreated) or SBP 140 mm Hg and/or BP 90 mm Hg (treated) TC 6.5 mmol/l (250 mg/dl) and TGs 4.5 mmol/l (400 mg/dl) years of age 3+ CVD risk factors: Male >55 years of age LVH or ECG abnormality Type 2 DM PAD or CVD (CVA or TIA) or family Hx of premature CHD Microalbuminuria/proteinuria Smoking TC/HDL >6 No history of CHD Sever et al, for the ASCOT Investigators. Lancet. 2003;361:

20 ASCOT LLA: Patient Population Risk Factor Profile All patients in ASCOT have hypertension plus 3 risk factors for CHD Hypertension Age 55 years Male Microalbumin/proteinuria Smoker Family history of early coronary disease Plasma TC:HDL-C 6 Type 2 diabetes Certain ECG abnormalities LVH Previous cerebrovascular events Peripheral vascular disease risk factors on average required for inclusion Patients with risk factor (%) Sever et al, for the ASCOT Investigators. Lancet. 2003;361:

21 DBP (mm Hg) SBP (mm Hg) Blood Pressure Changes 170 Baseline 164/95 Treated 138/ Atorvastatin 10 mg Placebo Years Sever et al, for the ASCOT Investigators. Lancet. 2003;361:

22 LDL cholesterol (mmol/l) (mg/dl) Total cholesterol (mmol/l) (mg/dl) Reductions in Total and LDL Cholesterol mmol/l 1.0 mmol/l % reduction Atorvastatin 10 mg Placebo % reduction 1.2 mmol/l 1.0 mmol/l Years Sever et al, for the ASCOT Investigators. Lancet. 2003;361:

23 Cumulative Incidence (%) Primary End Point: Nonfatal MI and Fatal CHD 4 Atorvastatin 10 mg Number of events 100 Placebo Number of events % reduction 2 1 HR = 0.64 ( ) p= Years Sever et al, for the ASCOT Investigators. Lancet. 2003;361:

24 Cumulative Incidence (%) 3 2 Secondary End Point: Fatal and Nonfatal Stroke Atorvastatin 10 mg Number of events 89 Placebo Number of events % reduction 1 HR = 0.73 ( ) p= Years Sever et al, for the ASCOT Investigators. Lancet. 2003;361:

25 Percentage with CHD event Landmark Statin Trials in 1º Prevention: LDL-C Levels vs Events 10 9 S = statin treated; P = placebo treated WOSCOPS-S WOSCOPS-P AFCAPS-S ASCOT-S AFCAPS-P ASCOT-P Primary prevention Pravastatin Lovastatin Atorvastatin (90) 2.8 (110) 3.4 (130) 3.9 (150) 4.4 (170) 4.9 (190) 5.4 (210) LDL-C, mmol/l (mg/dl) 35% LDL = 36% in Death + MI in 3.3 yrs 25% LDL = 40% in Death + MI in 5.2 yrs 26% LDL = 31% in Death + MI in 4.9 yrs Sever et al, for the ASCOT Investigators. Lancet. 2003;361:

26 Clinical trials that showed significant correlation between HDL and outcomes AFCAPS/TEXCAPS (AI and B/AI ratio, pooled data) 4S (pooled data) HHS VA-HIT DAIS HATS (FER HDL )

27 HDL and Triglycerides: Fibrate Trials N Drug Follow-up LDL TG HDL Results HHS 4081 Gemfibrozil 5.4 y -10% -43% +>10% 34% fatal/nonfatal CHD (P<0.02) BIP 3090 Bezafibrate 6.2 y -6.5% -21% +18% 9.4% nonfatal events, P=0.26 VA-HIT 2531 Gemfibrozil 5.1 y 0% -31% +6% 22% fatal/ nonfatal CHD P=0.006 DAIS 418 Fenofibrate 2 y -6% -29% +6% 23% CHD* (P=NS) *Not powered for clinical events. DAIS Investigators. Lancet. 2001;357: ; Haffner. Circulation. 2000;102:2-4; Frick. N Engl J Med. 1987;317:

28 Apo B and LDL-cholesterol Sample a Sample b LDL LDL LDL apo B LDL LDL LDL apo B LDL-C 3.0 mmol/l apo B 0.8 g/l LDL LDL LDL LDL-C 3.0 mmol/l apo B 1.6 g/l NOTE: apo B level does not correlate with serum TG level

29 apo B: Utility Not affected by fasting Not invalidated in cases of high TG Helps separate higher and lower risk patients with moderate TG increases Useful for monitoring therapy (decrease in # atherogenic particles, target < 0.9 g/l) May be extremely useful in stratifying patients with METABOLIC SYNDROME

30 Obesity* Trends Among US Adults BRFSS, 1991, 1995, and *BMI 30 or ~30 lbs overweight for 5 4 person. Mokdad et al. JAMA. 1999;282:16, 2001;286:10. No Data <10% 10%-14% 15%-19% 20%

31 Metabolic Syndrome

32 Metabolic Syndrome ( Death by a 1000 Lashes to Your Arteries ) 3 of the following abnormalities: waist circumferences 102 cm (men) 88 cm (women) serum triglycerides 1.7 mmol/l serum HDL-cholesterol 1.05 mmol/l (men) 1.30 mmol/l (women) blood pressure 130 / 85 mm Hg serum glucose 6.1 mmol/l

33 Is Diabetes a CVD Equivalent? There is a trade-off between low short-term risk vs high long term risk and the value of early vs delayed risk management Focus on glucose control has yielded suboptimal impact on macro-vascular complications

34 CV Mortality (%) Diabetes Is a CHD Equivalent No prior MI Prior MI N Nondiabetic Diabetic Haffner et al. N Engl J Med. 1998;339:

35 % Reduction Effect of Tight Glucose Control vs Tight BP Control on Events: UKPDS 0-10 Stroke Any Diabetic Endpoint Diabetes- Related Death Microvascular Complications * * * Tight glucose control Tight BP control (<150/85 mm Hg) * *P<0.05 compared with tight glucose control. Sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal MI, angina, heart failure, stroke, renal failure, amputation of 1 digit, vitreous hemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction. Death due to MI, sudden death, stroke, peripheral vascular disease, renal disease, hyperglycemia, or hypoglycemia. Bakris et al. Am J Kidney Dis. 2000;36:

36 High Lp(a) If well over I.U./L (>1,000?) treat LDL-C to < mmol/l particularly if other risk factors (BP) present or if TC/HDL >5 JAMA 1995;274:1771-4

37 A Plethora of Non-Lipid Markers of Risk 1. Vasodilatory Endothelial Dysfunction: Brachial Ultrasound Flow-Mediated Dilation. 2. Atherosclerosis Burden/End-organ Damage: Carotid IMT, # plaques (based on carotid US), IVUS, EBCT, advanced CT, MRI 3. General Inflammatory Marker: hs-c Reactive Protein 4. Markers of Inflamed Endothelium: ICAM, VCAM, e-selectin, vwf 5. Other: Homocysteine

38 Atherosclerosis Is an Inflammatory Disease LDL E-Selectin, P-Selectin L-Selectin, Integrins VCAM-1, ICAM-1 Monocyte OxLDL M-CSF MCP-1 Intima Other inflammatory triggers Libby et al. Circulation 2002;105: Macrophage Activation & Division Media Smooth Muscle Cell Migration

39 The Acute-Phase Response Pathway Proinflammatory Risk Factors Primary Pro-inflamatory Cytokines (eg, IL-1, TNF-a) ICAM-1 Selectins, HSPs, etc. Endothelium and other cells Circulation CRP SAA HSPs=heat shock proteins; SAA=serum amyloid-a. Adapted from Libby and Ridker. Circulation. 1999;100: IL-6 Messenger Cytokine Liver

40 Statins and Inflammation: CRP Additive With Lipids Ridker. Circulation. 2001;103: Relative Risk Data From NHANES Men Women

41 CRP and Metabolic Syndrome Ridker PM et al: Circulation 2003;107:

42 Recommendations for Clinical and Public Health Practice for CRP: Statement from AHA/CDC Class I : express CRP as mg/l Class II: CRP is an independent marker of risk which may help direct further evaluation and therapy in the primary prevention of CVD in patients at intermediate global risk (10-20%/10yr) unexplained and persistent values >10 mg/l should be evaluated for non-cv causes in patients with stable/acute CAD, CRP may be useful as an independent marker of prognosis for death, MI, restenosis measure CRP twice, two weeks apart (<1 = low RR, >3 = High RR)

43 B-Mode Ultrasound Skin External Internal Bifurcation Ultrasound pulse Near wall Far wall Kanters et al. Stroke. 1997;28:

44 Risk of MI (OR) Risk of Stroke (OR) Association of Carotid IMT With MI and Stroke < < N IMT (mm) N IMT (mm) Cutpoints used were the 40th, 60th, and 80th percentiles of the IMT distribution. Adjusted for age, sex, previous MI or stroke, body mass index, smoking, systolic BP, hypertension, total cholesterol, high-density lipoprotein cholesterol, and diabetes mellitus. 44 Bots et al. Circulation. 1997;96:

45 Peripheral Artery Endothelial Function Brachial Vasoreactivity Baseline Hyperemia Nitroglycerine (Ntg) 3.94 mm 4.56 mm 4.64 mm Vasodilation = 15.7% 17.8%

46 Left anterior oblique projection with cranial angulation by MSCT coronary angiography (A) and conventional coronary angiography (B) Nieman, Koen et al, The Lancet 2001; 357:

47 Whole-body 3D MRA in a 66-year old man Nieman, Koen et al, The Lancet 2001; 357:

48 New Focus Focus on 3 CHD, hard end-point risk levels as used in ATP III Treat to LDL and TC/HDL ratio (and apo B) targets A focus on TC/HDL and apo B ensures that TG problems associated with increased CHD risk should be adequately addressed

49 Thank you all.

50