DYSLIPIDEMIAS: TYPES I-V Thomas F. Whayne, Jr, MD, PhD, FACC Professor of Medicine (Cardiology) University of Kentucky March No conflicts to declare.

THE MAJOR LIPOPROTEINS CHYLOMICRONS. VERY LOW DENS. LIPOPROT. (VLDL). LOW DENS. LIPOPROT. (LDL). HIGH DENS. LIPOPROT. (HDL).

Normal Type I Type 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 STUDYDRUGDIABETIC SUBJECTS RESULTS: DIABETES HELSINKI HEART GEMFI- BROZIL 135 (4081) 65%  CARDIAC EVENTS, NS VA HITGEMFI- BROZIL 627 (2531) 24%  CAD DEATHS, MI AND CVA, < 0.05 DAISFENOFI- 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:

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