Management of Hyperlipidemia

Clinical Management Course

1/30/06

James M. May, M.D.

Department of Medicine

Vanderbilt University School of Medicine

GOALS :

• Rationale for treatment

• NCEP guidelines

• Diet therapy

• Drug therapy

-20

-26

5

-31-33

-22-25

-35

8

-34

-42

-30

-20

-28

5

-24

-19

-8

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

5

10

WOSCOPS (N=6,595) 4S (N=4,444) CARE (N=4,159)

N = number enrolled.

TC LDL-C

HDL-C

1o prevention 2o prevention 2o prevention

Summary of Effects of Lipid Lowering on Coronary Events in Recent Statin Trials

Nonfatal MI/CHD death

CHD death

All-cause mortality

%+

Risk of increased LDL and CHD: 30% change in = 30% change in CHD

Grundy, SM et al. . Circulation. 110:227-239, 2004.

Event Reduction and LDL: At What LDL Level Does Risk Go to Zero?

Primary Prevention Secondary Prevention

O’Keefe, JH, et al. Am. J. Cardiol. 43:2142-2146, 2004.

PI=placebo; Rx=treatment

Shepherd J et al. N Engl J Med. 1995;333:1301-1307.4S Study Group. Lancet. 1995;345:1274-1275.Sacks FM et al. N Engl J Med. 1996;335:1001-1009.Downs JR et al. JAMA. 1998;279:1615-1622.Tonkin A. Presented at AHA Scientific Sessions, 1997.

Mean LDL-C level at follow-up (mg/dL)

Relation Between CHD Events and LDL-C in Recent Statin Trials

0

5

10

15

20

25

30

90 110 130 150 170 190 210

% withCHD event CARE-Rx

LIPID-Rx

4S-Rx

CARE-PILIPID-PI

4S-PI

2° Prevention

1° Prevention

WOSCOPS-PI

WOSCOPS-RxAFCAPS/TexCAPS-Rx

AFCAPS/TexCAPS-PI

New Features of NCEP Guidelines: ATP III

• LDL remains primary treatment goal

• Diabetes: CHD risk equivalent

• Framingham projections of 10-year CHD risk

– Identify certain patients with multiple risk factors for more intensive treatment

• HDL cholesterol <40 mg/dL

– Raised from <35 mg/dL

• Multiple metabolic risk factors (metabolic syndrome)

Central obesityGlucose intolerance

AtherosclerosisHypertension

Polycystic ovary syndrome

Clinical Manifestations

Lipid:Carbohydrate:

Biochemical Abnormalities

Fibrinolysis:Insulin resistanceHyperinsulinemia

High TGLow HDL-C

Small, dense LDL particles

Increased PAI-1

The Insulin Resistance Syndrome

Laboratory: Fasting Lipid Profile

• 12-h fast

• Draw total cholesterol, HDL and triglycerides

• Calculate LDL = TC – HDL – TG/5

(accurate up to TG of 400 mg/dl)

• If TG > 400, measure LDL directly following ultracentrifugation.

Causes of Secondary Dyslipidemia

• Diabetes

• Hypothyroidism

• Obstructive liver disease

• Chronic renal failure

• Drugs: Raise TG, LDL and lower HDL: progestins anabolic steroids

thiazides beta-blockers corticosteroids

LDL Cholesterol Goals and Levels for Therapeutic Lifestyle Changes (TLC) and Drug Therapy

Risk CategoryLDL Level for

TLC

(mg/dL)

LDL Level for Drug Therapy

(mg/dL)

LDL Goal (mg/dL)

0–1 Risk Factor 160190

(160–189: drug optional)

<160

2+ Risk Factors (10-year risk 20%) 130

130(10-year risk 10–20%)

160(10-year risk <10%)

<130

CHD or CHD Risk Equivalents

(10-year risk >20%)100

130 (100–129: drug

optional)

<100(<70 if very high

risk patient)

Therapeutic Lifestyle Changes• TLC Diet

– Previous Step II Diet)• Saturated fats <7% of total calories• Dietary cholesterol <200 mg per day

– LDL-lowering therapeutic options• Plant stanols/sterols (2 g/day)• Viscous (soluble) fiber (10–25 g/day)

• Weight reduction • Increased physical activity

0 1000 2000 3000 40000

20

30

40

50

60

70

1 mg/dl increase = 450 Caloriesr = 0.987, p < 0.001

HD

L (m

g/dl

)

Exercise Calories/Week

Effects of Drug Therapy and Diet on Lipids

* 84% reached NCEP LDL target (<130 mg/dL)† 63% reached NCEP LDL-C target (<100 mg/dL)

Barnard RJ, et al. Exerpta Medica Brief Reports. 1997;1112-1114.

100

125

150

175

200

225

250

275

300

325 Pre-drugDrug

Drug + diet

TC (mg/dL) * †

P<0.01

1° Prevention (n=40) 2° Prevention (n=53)

Mechanism of action of Lipid-Lowering Agents on Lipoproteins

Agents LDL-C HDL-C VLDL-C

Resins 15-40% (modest ) secretion

Niacin 10-15% 30-40% 30-40%

Fibric acids (small ) 10-15% 50%

Statins 25-50% 5-8% 20-50%

Ezetimibe 18-20% 5-8% 15-20%

* Significantly less than atorvastatin 10 mg (P<0.02).† Significantly less than atorvastatin 20 mg (P<0.01).‡ Significantly greater than mg-equivalent dose of comparative agents (P0.01).Jones P et al. Am J Cardiol. 1998;81:582-587.

-60

-50

-40

-30

-20

-10

0

0 10 20 30 40 50 60 70 80 90

Atorvastatin

Fluvastatin

Lovastatin

Pravastatin

Simvastatin

Dose range (mg)

Mean% LDL-Creduction

*

**

*

** *

†

† †‡

‡

‡

The CURVES Trial: A Comparison of LDL-C Lowering Among Statins

-70

-60

-50

-40

-30

-20

-10

0

Baseline Week 2 Week 4 Last DB visit

Mean % in LDL-C

P<0.05.DB=double blind.

Nawrocki JW et al. Arterioscler Thromb Vasc Biol. 1995;15:678-682.

10 mg20 mg

40 mg

80 mg

Atorvastatin Dose-Response Relationship in Primary Hypercholesterolemia

Drug Therapy in Primary Prevention

If LDL goal not achieved, intensifyLDL-lowering therapy

Increase statin or add ezetimibe (or a bile acid sequestrant)

6 wks

Rx: statin, or if severe LDL increase, statin + ezetimibe

Initiate LDL-lowering drug therapy

6 wks

If LDL goal not achieved, intensify drug therapy or refer to a lipid specialist

Monitor response and adherence to therapy

If LDL goal achieved, treat other lipid risk factors

Q 4-6 mos

SUMMARY and CONCLUSIONS:

• LDL Lowering remains primary

• Stress: HDL, diabetes, & diet/exercise

• AHA step II is standard diet

• Statins as primary therapy

• Treat triglycerides, low HDL, especially if part of the “metabolic syndrome”