Biochemistry of Dyslipidemia
 Robert J. Flaherty, MD
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Dave is a 50 year-old white male with the following diagnoses:
  • Obesity: Height 5’10", weight 205 pounds, BMI 30 (minimal risk 18-24)
  • Type 2 diabetes: Fasting blood sugar 150 (desirable <100). Hgb A1c 8.0 (desirable <6.5)
  • Hypertension: Blood pressure 150/95 (desirable <130/80)
  • Hyperlipidemia: Total cholesterol 240 (desirable <200), LDL cholesterol 140 (desirable <100), HDL cholesterol 30 (desirable >40)
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Disease overview: Dyslipidemia
  • Risks of dyslipidemia
    • Cardiovascular disease (CVD): coronary heart disease (CHD), MI, stroke, atherosclerosis
      • In 2003
        • Over 71 million in US with CVD (34% of adult population - 50% men, 50% women)
        • Over 900,000 deaths/y (47% men/53% women)
          • $403 billion/y
    • Hypercholesterolemia
      • Cholesterol levels
        • <200 – Desirable
        • 200-239 – Borderline high
        • >= 240 - High
      • Relationship between elevated cholesterol and coronary heart disease has been recognized for many years
      • But separating out the individual roles and importance of cholesterol, each lipoprotein and triglycerides is difficult because of overlapping abnormalities and effects
    • Hypertriglyceridemia
      • Triglyceride levels
        • <150 – Normal
        • 150-199 – Borderline high
        • 200-499 – High
        • >=500 – Very high
      • Elevated serum triglycerides are associated with increased risk for CHD, independent of total cholesterol, HDL and LDL levels (ATP III)
      • In addition, elevated triglycerides are commonly associated with other lipid and nonlipid risk factors (ATP III)
    • High LDL (Low Density Lipoprotein)
      • LDL levels
        • <100 – Optimal (?<=70) (very low level of atherogenesis)
        • 100-129 – Near optimal/above optimal (atherogenesis occurs at and above this level)
        • 130-159 – Borderline high
        • 160-189 – High
        • >=190 – Very high
      • Multiple lines of evidence from experimental animals, laboratory investigations, epidemiology, genetic forms of hypercholesterolemia, and controlled clinical trials indicate a strong causal relationship between elevated LDL cholesterol and CHD (ATP III)
    • Low HDL (High Density Lipoprotein)
      • HDL levels
        • <=40 – Low
        • >=60 - High
      • A low HDL-cholesterol level is strongly and inversely associated with risk for CHD (ATP III)
      • May not reflect effect of HDL itself, but association with other risk factors
        • Elevated triglycerides
        • Remnant lipoproteins (Intermediate density lipoproteins = IDL)
        • Small, dense LDL particles
        • Insulin resistance
    • High VLDL (Very Low Density Lipoprotein) & High IDL (Intermediate Density Lipoprotein)
      • Not usually measured, but linked closely to triglyceride levels
      • VLDL highly atherogenic
      • “Non-HDL cholesterol” (= total cholesterol – HDL) reflects levels of LDL + intermediate density lipoproteins (IDL) + VLDL, and may more accurately reflect CHD risk than LDL alone
    • But don’t forget the non-lipid-related CVD risk factors
      • Modifiable
        • Hypertension
        • Cigarette smoking
        • Thrombogenic/hemostatic state
        • Diabetes
        • Obesity
        • Physical inactivity
        • Atherogenic diet
      • Non-modifiable
        • Age
        • Male sex
        • Family history of premature CHD
  • Benefits of treatment
    • Disease Oriented Evidence/Outcomes (DOEs)
      • Lower cholesterol levels
      • Lower triglyceride levels
      • Lower LDL levels
      • Elevated HDL levels
    • Patient Oriented Evidence/Outcomes (POEMs)
      • Lowering total cholesterol
        • Older studies showed lowering total cholesterol decreased CV events
        • LDL levels were not specifically identified
      • Lowering triglycerides
        • Appears to lower CVD risk, but may be related to triglycerides being a marker for other lipid and nonlipid risk factors
      • Lowering LDL
        • Reduces risk for CHD in primary and secondary prevention, particularly when LDL-cholesterol levels are reduced to <130 mg/dL (ATP III)
        • Even lower may be even better: In patients with stable coronary heart disease, lowering LDL below 80 mg/dL with high dose atorvastatin decreased cardiovascular events, as compared to low dose atorvastatin which lowered LDL to ~100 mg/dl (NNT = 45 for 4.9 years, but NNH = 43)
      • Raising HDL
        • Raising HDL by treatment does not decrease CVD events, CVD mortality or all cause mortality
      • Intensive cholesterol-lowering therapy may be more effective in preventing coronary events than angioplasty
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Normal Lipoprotein Biochemistry and Physiology (See Figure 1)
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FIgure 1: Normal Lipoprotein Biochemistry and Physiology 
  • Exogenous pathway
    • Source: Dietary
    • Pancreas secretes lipases into bile to break down fat into fatty acids
    • Liver secretes bile acids (mostly cholesterol) into bile
    • Intestinal brush border cells esterify fatty acids into triglycerides and package them with cholesterol into chylomicrons
    • Chylomicrons are secreted into lymph system and transported to blood stream, then to capillaries
      • ~80% triglycerides/~15% cholesterol (cholesteryl ester)
    • Capillary lipoprotein lipase strips off some fatty acids for peripheral cell use
    • Chylomicron remnants transported to liver via bloodstream
  • Endogenous pathway
    • Liver creates VLDL to transport triglycerides and cholesterol to peripheral tissues
      • VLDL
        • Contains ~80% triglycerides/~15% cholesterol
        • Apoproteins: apo B-100, apo Cs, apo E
        • Makes up 10-15% of total serum cholesterol
        • Can directly contribute some of its cholesterol to HDL for return to liver
        • Emerging understanding of its role in atherogenesis
      • IDL
        • Contains ~50% triglycerides/~50% cholesterol
        • Not specifically tested for, but reflected in total cholesterol lab test result
        • Remnant of VLDL after fatty acids removed by capillary lipoprotein lipase
        • Returned to liver or converted into LDL
        • Clinical significance unclear
      • LDL
        • Contains 80+% cholesterol
        • Makes up 60-70% of total serum cholesterol
        • Apoprotein: apo B-100
        • Taken up by peripheral cells
          • Stored
          • Affects peripheral cell cholesterol synthesis, which involves HMG Co-A reductase
        • Is the major athrogenic lipoprotein
        • Smaller LDL particles are more atherogenic
    • Liver and small intestine create nascent HDL to transport cholesterol from peripheral cell stores to liver
      • HDL
        • Contains almost 100% cholesterol
        • Makes up 20-30% of total serum cholesterol
        • Apoproteins: apo A-I and apo A-II
        • Removes cholesterol from peripheral cells 
        • Also has anti-oxidant and anti-inflammatory properties
        • May protect against development of atherosclerosis by removing cholesterol from foam cells, as low HDL levels associated with higher risk of atherosclerosis
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Disordered Biochemistry and Physiology
  • The inflammatory pathogenesis of atherosclerosis (See Figure 2)
Figure 2: The Inflammatory Pathogenesis of Atherosclerosis
    • Endothelial activation
      • Stressors (smoking, hypertension, mechanical stress on vessel walls, hyperglycemia, free fatty acids and reactive oxygen species (ROxS)) make endothelium “sticky” for activated leukocytes
      • Activated endothelium also generates ROxS
    • Leukocyte activation
      • Lipoproteins (chylomicrons, VLDL, LDL, VLDL remnants/IDL) activate resting leukocytes in bloodstream
      • Activated leukocytes attach to activated endothelial cells
      • Attachment causes leukocytes to release ROxS and tumor necrosis factor-a, which activate more endothelial cells and damage the endothelial cells
      • Attached monocytes and lymphocytes squeeze between endothelial cells and enter vessel wall
      • Monocytes are activated and differentiate into macrophages
    • Invasion of the lipoproteins
      • LDL and VLDL remnants/IDL are transported by endothelial cells into the vessel wall
      • LDL is oxidized into highly atherogenic oxidized LDL (Ox-LDL)
    • Rise of the foam cells
      • Ox-LDL and remnants are engulfed by macrophages to form foam cells
      • Foam cells form atheromatous plaques
      • Foam cells die and leave their ingested cholesterol and triglycerides as components of the plaque
      • HDL can remove some of this cholesterol and return it to the liver
    • Inflammation and recruitment
      • Macrophages also activate endothelial cells to produce inflammatory chemicals (IL-6, IL-8, MCP-1) which attract resting leukocytes, which are then activated by lipoproteins, and the process starts again
      • Aspirin can block the inflammatory chemical cascade
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Metabolic and anatomic consequences
  • Atheroma development and plaque fracture (See Figure 3)
Figure 3: Atheroma Development and Plaque Fracture
    • Atheromatous plaques grow on the vessel wall 
    • Plumbing problem: Physically obstruct vessel lumen
    • Thrombosis problem: Damaged endothelial cells die, fracturing the plaque, exposing thrombogenic chemicals and stimulating clot formation
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Therapeutic approaches (See Figures 1 and 2)
  • Diet
    • Actions: 
      • Saturated fat is the principal dietary determinant of LDL and total cholesterol levels
      • Dietary trans-unsaturated (partially hydrogenated) fatty acids increase LDL, reduce HDL cholesterol and are pro-inflammatory

Two 18-carbon fatty acids with a single double bond
        • Hydrogenation process involves heating vegetable omega-6 oils to high temperatures, which forms trans-fatty acids
        • Have replaced animal fats in most processed foods because of longer shelf life, stability in deep frying, improved taste
        • trans-FA act physiologically more like saturated fatty acids
        • Naturally occurring trans-FA accounts for 0.5% of dietary calories
        • Industrially produced trans-FA accounts for 2-3% of dietary calories
        • A 2% increase in calories from trans-FA is associated with a 23% increase in CHD – more than any other macronutrient
      • Polyunsaturated and monounsaturated fatty acids actively lower total cholesterol levels
      • Dietary cholesterol can increase total and LDL cholesterol levels, although to a lesser extent than saturated fat
      • Hence, dietary modifications to decrease cholesterol and bad fatty acid intake
    • Examples: Many different kinds
    • Results: 
      • Some diets can lower total and LDL cholesterol
      • But low-fat diets can increase plasma triglycerides and decrease HDL
      • Diets high in monounsaturated fatty acids can lower both total cholesterol and triglycerides
    • Advantages: 
      • Some evidence suggests the Mediterranean diet decreases CV events, possibly due to fiber, olive oil, n-3 fatty acids
      • Most can be tasty
      • May offer other advantages (e.g. lowering BP, weight)
      • Mediterranean diet relatively cheap
    • Disadvantages:
      • In general, diets do not decrease CV or overall mortality
      • Some can be expensive
      • Sometimes difficult to adopt and maintain a different diet
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  • Exercise (Ex)
    • Actions: 
      • Not clear
    • Examples: Aerobic-type exercise
    • Results: 
      • Exercise can raise HDL cholesterol and lower total cholesterol, LDL cholesterol and triglycerides
      • Or maybe not
    • Advantages: 
      • Primary prevention: Probably decreases CV events and death
      • Secondary prevention: Probably decreases CV events and death, especially as part of a multi-factorial intervention program
         
      • Other benefits (e.g. lowering BP, weight)
      • Buff
      • Cheap
    • Disadvantages:
      • Potential for injury
      • Difficult to maintain
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  • Statins/HMG Co-A reductase inhibitors (Stat)
    • Actions: 
      • Inhibit rate limiting step in cholesterol synthesis
      • Increase LDL receptor activity, thus increased LDL clearance from blood
      • Thus, decrease amount of peripheral cholesterol presented to liver for recycling into VLDL and ultimately LDL
      • But also decrease mevalonic acid production of non-steroidal isoprenoid compounds which are involved with cell membrane signaling, possibly accounting for non-lipid-related effects
      • Pleiotropic effects may be more important than lipid effects
        • Improve endothelial function
        • Reduce inflammation (e.g. reduce CRP levels)
        • Stabilize plaques
        • Decrease platelet aggregation
        • Decrease thrombin formation
    • Examples: Atorvastatin (Lipitor), lovastatin (Mevacor, generic), pravastatin (Pravachol), simvastatin (Zocor)
    • Results: 
      • Lower LDL
      • Modestly raise HDL and lower triglycerides
      • May reverse or slow progression of atherosclerosis
    • Advantages: 
      • Decrease CV events in patients at all risk levels
        • All seem effective 
          • Primary prevention NNT 855 for 1 year (mortality) and 228 for 3.3 years (CV events)
          • However, a newer meta-analysis on primary prevention suggests a decrease in CV events and revascularizations, but no decrease in CHD mortality or overall mortality
          • Secondary prevention NNT 248 for one year (mortality) and 50 for 4.4 years (CV events)
        • ? Atorvistatin and simvistatin most effective
        • Atorvastatin shown to be effective for primary prevention of CV events, but not all-cause mortality or need for coronary revascularization, in type 2 diabetics (NNT 32 for 3.9 years)
      • Other benefits
        • Prevents stroke (NNT 617-2778 for 1 year), but not as impressively as other CV events
        • Improves acute morbidity and mortality in MI
        • Maintains renal function
        • Possibly reduces risk of colon and prostate cancer, osteoporosis, Alzheimer’s disease
      • Inexpensive (generic)
    • Disadvantages:
      • Usually well tolerated, but side effects include GI, headache, rash, fatigue, muscle aches/weakness/injury, hepatic injury 
        • But pre-existing LFT elevations do not increase risk of taking statins, even over 10 times upper limit of normal
      • Adverse effects with rosuvastatin (Crestor) are 2-10 times more common than with other statins
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  • n-3 Fatty acids/omega-3 Fatty acids (o-3FA)
    • Actions: 
      • Are polyunsaturated fatty acids
      • Reduce hepatic triglyceride production
      • Increase triglyceride clearance
      • Pleiotropic effects: Anti-arrhythmic (or maybe not), plaque stabilizing, anti-inflammatory 
        • Inflammation partly due to altered ratio of ingested n-3 (omega-3) and n-6 (omega-6) fatty acids (See Figure 4)
        • Prehistoric dietary ratio of n-3 to n-6 fatty acids was about 1:1
        • Modern dietary ratio is about 1:20 or higher
        • Kinetic shift to the production pro-inflammatory chemicals
Figure 4: Fatty Acids and Inflammation
    • Examples: Fish oil, Omacor
    • Results: 
      • Reduce triglycerides
      • Little effect on total cholesterol, LDL or short-term HDL levels
      • May increase HDL levels long-term
    • Advantages: 
      • Decreased CV morbidity and mortality
        • Secondary prevention NNT 16-44 for 4.4 years
        • Primary prevention ?
        • Benefit may be from pleiotropic effects, since magnitude of benefit does not correlate with level of lipoprotein improvement
      • Cheap
    • Disadvantages:
      • Taste
      • Fishy burps
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  • Bile acid sequestrants/Resins (Res)
    • Actions: 
      • Bind bile acids in intestine
        • Interrupt enterohepatic circulation of cholesterol
        • Increase clearance of cholesterol from blood
    • Examples: Cholestyramine (Questran, generic), colestipol (Colestid), colesevelam (Welchol)
    • Results: 
      • Decreased total and LDL cholesterol
      • Increase HDL
      • May increase triglycerides
    • Advantages: 
      • Reduced combined non-fatal MI and CV mortality (NNT 65 for 7.4 years) in early study
    • Disadvantages:
      • Later studies show
        • Minimal, if any, reduction in CV mortality
        • No reduction in cardiac or overall mortality
      • Constipation, heartburn, nausea, bloating
        • More common with colestipol and cholestyramine
      • Moderately expensive to expensive
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  • Fibrate/Fibric acid derivatives (Fib) 
    • Actions: 
      • Activate the nuclear transcription factor peroxisome proliferator activated receptor-a (PPAR-a)
      • Increase expression of lipoprotein lipase, breaking down triglycerides into free fatty acids in the capillaries
      • Decrease apoC-III, thus decreasing VLDL
      • Increase expression of apoA-I and apoA-II, increasing HDL
      • Pleotropic effects: Anti-inflammatory, anti-thrombotic
    • Examples: Gemfibrozil (Lopid), fenofibrate (Tricor, Lofibra, generic) 
    • Results: 
      • Lower triglycerides
      • Raise HDL
      • May lower or raise LDL
      • Shift toward production of larger LDL particles (less atherogenic)
      • Some decreased progression of atheroma formation
    • Advantages: 
      • Decrease CV events (primary and secondary)
        • Especially in pre-existing cardiac disease, obesity, insulin resistance, type 2 DM, high triglycerides, low HDL (CV events NNT = 33 for 4 yrs)
    • Disadvantages:
      • Does not decrease CV mortality or all-cause mortality
      • Increases the risk of non-cardiac mortality
      • GI symptoms, cholelithiasis, hepatitis, myositis
        • Side effects more common with gemfibrozil
      • Moderately expensive
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  • Niacin/Nicotinic acid (Nia)
    • Actions: 
      • Decreases VLDL production
      • Increases ApoA1, thus increasing HDL
      • Decreases lipolysis in adipose tissue
      • Activates PPAR-a
      • Pleiotropic effects: Antioxidant (prevents LDL oxidation in endothelium), anti-inflammatory.
    • Examples: Immediate-release niacin (generic), slow-release (Niaspan, Slo-Niacin)
    • Results: 
      • Niacin does it all!
      • Increases HDL
      • Decreases total cholesterol
      • Decreases LDL, especially small athrogenic forms
      • Decreases triglycerides
      • Causes regression of atheromas
    • Advantages: 
      • Decreases CV events
        • Secondary prevention studies, usually with another anti-lipid drug
        • Benefit for primary prevention unknown
      • Cheap
    • Disadvantages:
      • Does not decrease CV or overall mortality
      • Skin flushing, pruritis
        • Aspirin pre-treatment helps
        • Improves with time
      • Glucose intolerance
        • Especially with high doses
        • Can be safely used in diabetics with close glucose monitoring
      • GI symptoms, hepatic toxicity, blurred vision, fatigue
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    • Cholesterol absorption inhibitors (CAI)
      • Actions: 
        • Blocks absorption of dietary and biliary cholesterol by intestinal brush border cells
      • Examples: Ezetimibe (Zetia), ezetimibe+simvastatin (Vytorin)
      • Results: 
        • Reduces total and LDL cholesterol
        • Minor effects on triglycerides and HDL
      • Advantages: 
        • Allows lower dose of statin when combined with a statin
        • ? A hammer looking for a nail
      • Disadvantages:
        • Not yet shown to improve CV outcomes or mortality
        • Even combined with a statin, is no better at improving lipoprotein levels than a statin alone
        • Flatulence, diarrhea, myositis, hepatitis, pancreatitis, thrombocytopenia
        • Moderately expensive