DYSLIPIDEMIAS:TYPES I-V

Thomas F. Whayne, Jr, MD, PhD, FACC

Professor of Medicine (Cardiology)

University of Kentucky

March 2011.

E-Mail: twhayn0@uky.edu.

No conflicts to declare.

THE MAJOR LIPOPROTEINS

• CHYLOMICRONS.• VERY LOW DENS. LIPOPROT. (VLDL). • LOW DENS. LIPOPROT. (LDL) .• HIGH DENS. LIPOPROT. (HDL) .

NormalType

IType IIA

Type IIB

Type III

Type IV

Type V

Before UC After UC

Tube Plain

VLDL

LDL

HDL

Tube with KB

VLDL

LDL

HDL

TYPE I

• RARE GENETIC DISORDER.

• HYPERCHYLOMICRONEMIA.

• LIPOPROTEIN LIPASE DEFICIENCY.

TYPE I: TREATMENT

• RESTRICTION OF FATS.

• PANCREATITIS: NPO.

• MEDIUM CHAIN FATTY ACID TRIGLYCERIDES.

TYPE II-A HYPERLIPOPROTEINEMIA

AUTOSOMAL DOMINANT.– HETEROZYGOTES: 1 IN 500.– HOMOZYGOTES: 1 IN 1,000,000.

TYPE II-A IS ALSO:

• POLYGENIC.

• SPORADIC.

• POSSIBLY ACQUIRED

TYPE II-A

• ACCELERATED ATHEROSCLEROSIS, ESPECIALLY CORONARY.

• TENDON XANTHOMAS.

• TUBEROUS XANTHOMAS.

• XANTHELASMA.

• CORNEAL ARCUS.

EXTREME EXAMPLE OF TYPE II-A HYPERLIPOPROTEINEMIA

STORMY JONES: AGE 10.

TYPE II-B

ACCELERATED ATHEROSCLEROSIS: CORONARY AND PERIPHERAL

TYPES IIA/IIB: TREATMENT

• STATINS ESPECIALLY.

• BILE ACID BINDING RESINS, ESPECIALLY COLESEVELAM.

• NICOTINIC ACID (NIASPAN®).

• ZETIA.

• POLICOSANOL.

• LDL APHERESIS.

TYPE III

• ACCELERATED ATHEROSCLEROSIS, ESPECIALLY PERIPHERAL.

• PALMAR XANTHOMAS.

• TUBEROUS XANTHOMAS.

TYPE III

APO E IN LIVER RECEPTORS IS ABNORMAL OR DEFICIENT FOR:– LOW DENS. LIPOPROTEINS (LDL).– INTERMED. DENS. LIPOPROTEINS (IDL).– CHYLOMICRON REMNANTS.

TYPE III TREATMENT

• LOW CHOLESTEROL UNSATURATED FAT DIET.

• SOME CARBOHYDRATE (SIMPLE SUGARS) RESTRICTION.

• CLOFIBRATE (ATROMID).• GEMFIBROZIL (LOPID).• FENOFIBRATE (TRICOR).• STATIN.

TYPE IV HYPERLIPOPROTEINEMIA

• ALSO CALLED FAMILIAL HYPERTRIGLYCERIDEMIA.

• ACCELERATED ATHEROSCLEROSIS, ESPECIALLY PERIPHERAL.

TYPE IV: TREATMENT

• FENOFIBRATE.• NICOTINIC ACID (NIASPAN®).• OMEGA FATTY ACIDS (LOVAZA®).• METFORMIN.• PIOGLITAZONE.• STATINS.• EZETIMIBE.• INSULIN.

TYPE V

• INCREASED CHYLOMICRONS AND VLDL.

• CAN BE RARE GENETIC DISORDER.

• CAN BE MORE FREQUENTLY SEEN IN DIABETES, EVEN WITH MILD INCREASE IN PLASMA GLUCOSE.

TYPE V: TREATMENT

• CONTROL DIABETES.

• FENOFIBRATE.

• NICOTINIC ACID (NIASPAN®).

• OMEGA FATTY ACIDS (LOVAZA®).

• METFORMIN.

• PIOGLITAZONE.

• INSULIN.

DYSLILPIDEMIA IN DIABETES:TYPICAL PATTERN

• HIGH LEVELS OF TRIGLYCERIDES.

• LOW LEVELS OF HDL.

• PREPONDERANCE OF SMALL DENSE LDL.

SMALL, DENSE LDL

• ASSOCIATED WITH 3X RISK OF CHD.

• INCREASED ATHEROGENICITY:– FASTER ENTRY INTO BLD. VESSEL WALL. BINDING TO LDL RECEPTOR.– INCREASED SUSCEPTIBILITY TO

OXIDATION.

TRIGLYCERIDES IN DIABETES

• HIGH TRIGLYCERIDE LEVELS OCCUR MAINLY IN VLDL BUT ALSO IN CHYLOMICRONS.

• ELEVATED TRIGLYCERIDE LEVELS RESULT FROM:– OVERPRODUCTION OF VLDL.– IMPAIRED LIPOLYSIS OF

TRIGLYCERIDES (INSULIN IS AN LPL COFACTOR).

ADA RATIONALE FOR Rx OF DYSLIPIDEMIA IN DIABETES

• THERE IS RISK OF CHD BECAUSE OF DYSLIPIDEMIA.

• DIABETIC DYSLIPIDEMIA FREQUENTLY CHARACTERIZED BY TRIGLYCERIDES, HDL AND SMALL, DENSE LDL.

• Rx OF DIABETIC DYSLIPIDEMIA MAY REDUCE RISK OF CHD.

IMPROVED CONTROL OF HYPERGLYCEMIA

• CAN REDUCE DYSLIPIDEMIA.

• MAY RESULT IN ATHEROGENIC DENSE LDL.

• COMPLETE REVERSAL OF DYSLIPIDEMIA USUALLY NOT ACHIEVABLE.

RESPONSE OF DENSE LDL TO MEDICATION

• FIBRATES AND NICOTINIC ACID (NIASPAN®) SHIFT THESE DENSE LDL TO A LARGER SIZE LDL PARTICLE.

• STATINS ARE NOT EFFECTIVE IN FAVORABLE SHIFT OF DENSE LDL TO LARGER, LESS DENSE LDL PARTICLE.

FIBRATES IN TYPE II DIABETICS

STUDY DRUG DIABETIC SUBJECTS

RESULTS:

DIABETES

HELSINKI HEART

GEMFI-BROZIL

135 (4081) 65% CARDIAC

EVENTS, NS

VA HIT GEMFI-BROZIL

627 (2531) 24% CAD DEATHS, MI AND CVA, < 0.05

DAIS FENOFI-BRATE

418(418) 23% CV EVENTS, DEATHS (PRELIM.)

Syndrome X, Metabolic Syndrome or Cardiovascular Dysmetabolic Syndrome

• Obesity.

• Hypertriglyceridemia.

• Low HDL.

• Increased Dense LDL.

• Hypertension.

• Insulin Resistance.

• Hyperuricemia.

• Increased PAI-1.

AT LEAST 3 OF THE FOLLOWING 5 PRESENT†:TG 150 mg/dl.HDL < 40 mg/dl in men and < 50 mg/dl in women .BP 130/85 mm/Hg.Waist girth > 102 cm (men) and > 88 cm (women).Fasting glucose 100 mg/dl.

OTHER COMPONENTS: dense LDL, Insulin resistance, Hyperuricemia, PAI-1, hsCRP, Tissue necrosis factor-α Interleukin-6, Resistin, and Adiponectin.

METABOLIC SYNDROME, SYNDROME X

or CV DYSMETABOLIC SYNDROME

†Grundy SM, et al. Circulation 2005;112:2735-2752.

Adapted from: Ford ES, et al. JAMA 2002;287:356-359.

47 million or 23% of US adults have the metabolic syndrome

Metabolic Syndrome: Prevalence Increases with Age

MARKED HYPERTRIGLYCERIDEMIA

CAN OCCUR FROM RETROVIRUS Rx IN HIV

PATIENTS

Thiazides:

• Marked elevation of triglycerides and VLDL can occur.

• Increased total cholesterol and LDL.

• Little effect on HDL.

ESTROGEN

SPORADICALLY AND UNPREDICTABLY, ESTROGEN MAY CAUSE A MARKED ELEVATION IN TRIGLYCERIDES.

BETA BLOCKERS

• Increase triglycerides and VLDL.

• Decrease HDL.

• Less significant increase in Total Cholesterol and LDL.

• Beta Blockers with ISA may have a less pronounced effect.

CONCLUSION

MULTIPLE APPROACHES AVAILABLE TO ACHIEVE GOOD BLOOD LIPID CONTROL AND THEREBY AVOID MULTIPLE CLINICAL PROBLEMS INCLUDING SEQUELAE OF CORONARY ATHEROSCLEROSIS.