Dyslipidemia

Dyslipidemia

Physiology and metabolism # Extrinsic pathway;TG and chylomicron after meal inter lymphatics to thoracic duct, to circulation (capillaries), LPL help extract FFA to tissue for oxidation and TG formation, rest go to liver(chyl. Remnant) up taken for metabolism. # Intrinsic; liver form VLDL to circulation (LPL) where IDL formed, more TG extracted to taken to liver or changed to LDL to tissue LDL-R for use. LDL also formed in the liver by HMGCoA aid, LDL-R also found in liver. # excess cholesterol in tissue by aid of LCAT incorporated in HDL to the liver.

Exogenous Pathway of Lipid Metabolism

Vessel wall

Cholest AA FA P, glycerol

Endogenous Pathway of Lipid Metabolism

Key Enzymes and Cofactors in Lipid Metabolism
HMG-CoA reductase-reduces HMG-CoA to mevalonic acid in the rate-limiting step of cholesterol biosynthesis (mainly liver and intestine) Lipoprotein Lipase- digests TG core of CMC and VLDL Hepatic Lipase-conversion of IDL to LDL CETP-transfers cholesteryl esters from HDL to other lipoproteins in exchange for TG LCAT(lecithin cholesterol acyl transferase) conversion of cholesterol to cholesterol esters Apolipoprotein A-major protein of HDL activating many reactions Apo-B-major protein of VLDL, IDL, and LDL Apo-CII and Apo E obtained from HDL by CMC and VLDL for activation of LPL and receptor recognition respectively

*lipoprotein LDL,IDL,chyl. Remnant are major risk factors for IHD, increase concentration and reduce diameter favor accumulation, oxidation and glycation modify it so not removed easly and accumulated in foam cells. *lipoprotein particle contain envelop of apolipoprotein, free cholesterol, and phospholipid with core of TG and esterified cholesterol.

LDL Oxidation and Atherosclerosis

DYSLIPIDEMIA(A consequence of abnormal lipoprotein metabolism)

Elevated Total Cholesterol (TC) Elevated Low-density lipoproteins (LDL) Elevated triglycerides (TG) (VLDL) Decreased High-density lipoproteins (HDL) Small dense LDL (apo B)

Dyslipidemia

Causes #primary *predominant hypercholesterolemia -polygenic(commonest) -familial (LDL-R defect)- tendon xanthoma -defective apo 100,narc-I protease -hyperalphalipoproteinemia *predominant hypertriglyceridemia -polygenic -LPL deficiency -familial hypertriglyceridemia *mixed hyperlipedemia -polygenic -familial combined hyperlipidemia, some of family hyperchol, some hyperTG -dysbetalipoproteinemia

Dyslipidemia

Causes #secondary *hypercholesterolemia -hypothyroidism -pregnancy -cholestatic liver disease -drugs( diuretics, cyclosporin, steroid , androgen) -nephrotic, anorexia nervosa, hyperparathyroidism, porphyries. *hypertriglyceridemia - type 2 DM, abdominal obesity - chronic renal and liver disease - alcohol -drugs(B- blockers, retinoids, steroids)

Measurement of Lipoproteins

Lipoprotein analysis 12-14 hours fasting TC and HDL-C can be measured fasting or non-fastingLDL-Cholesterol = Total cholesterol –VLDL (1/5 TG)-HDLValidity depends on TG <400 mg/dLMeasured directly if patients have profound hypertrigErrors in TC, HDL, and TG can affect values Non-HDL cholesterol= TC – HDL-CAll cholesterol in atherogenic lipoproteins incl LDL, Lipoprotein a, IDL, VLDLAcute phase response (i.e. MI, surgical trauma or infection)Can reduce levels of TC, HDL, LDL, apo A+B through impairment of hepatic lipoprotein production and metabolismRaise Lpa and TGLipoprotein analysis should be done as outpatient one month after event

New Guidelines for LDL Goal

Risk category
Goal LDL (mg/Dl)
CHD (CHD risk equivalent)
<100 <70 optional
2 or more major risk factors + 10 yr >20%
<100 <70 optional
2 or more major risk factors +10 yr 10-20%
<130 <100 optional
2 or more major risk factors +10 yr risk <10% 0-1 major risk
<130 <160

Dyslipidemia

Management ## nonpharmacological therapy; *reduce intake of saturated and trans-unsaturated fat *reduce cholesterol intake *reduce dense energy food *reduce alcohol *increase vegetables, unrefined carbohydrates, fibers, fruits *increase fish, omega 3 FA *wt loss, exercise, smoking and dealing with other modifiable CV risk factors *these measures more effective in hyperTG, usually start with in 4w. ##indication of therapy and level of control; *LDL IHD(eq. DM) 100mg, more than 2 risk factors 130, less 160. *high TG(200mg) and low HDL(40mg) are independent risk factors for IHD

Dyslipidemia

## pharmacological management*statin (HMGCoARI) livo, simva, atorva. SE. myopathy(CK),hepatitis(ALT) reduce chol synth, reduce LDL 60%, TG 40%, increase HDL 10%.*ezetimibe; cholesterol absorption inhibitor(NPC1L1), reduce LDL 20%*colestyramin(bile acid sequestrant) LDL 15%*nicotinic acid(B3); decrease chol, TG, increase HDL,(flush,gout,DM,vomiting)*fibrate;(PPAR)-alpha, reduce synthesis of TG, FA(50%), gemfibrozil, fenfibrate*omega 3 FA; present in fish oil(30%)reduce TG and platelet aggregation.##how to treat*hyperchol; statin—ezetimibe—colestyramin—nicotin. *hyperTG; fibrate—fis oil—nicotin.*mixed; statin+fish oil—statin+fibrate.

Statins

Competitive inhibitors of HMG CoA reductase, rate-limiting step in cholesterol biosynthesis Reduction in intrahepatic cholesterol leading to increased LDL receptor turnover Most powerful for lowering LDL cholesterol Modest effect on raising HDL Reduction in TG due to decreased VLDL synthesis and clearance of VLDL remnants by apo B/E (LDL) receptors Reduction in oxidized and small dense LDL subfractions and reduce remnant lipoprotein cholesterol levels (reduction of CE transfer from LDL to VLDL)

Adverse Effects of Statins

In general, less than with other agents. Fairly tolerable and safe Myopathy Ranges from myalgias (2-11%), myositis(0.5%) to rhabdomyolysis (<0.1%) (possibly ARF) Few weeks-4 months onset Symptoms and CK should normalize over days to one month after d/c Increased risk in ARF/CRF Obstructive liver disease Hypothyroidism Concomittant use of drugs interfering with CYP3A4?? Gemfibrozil combined therapy Hepatic 0.5 to 3% persistent elevations in amino-transferases in first 3 months and dose-dependent FDA recommends LFTs before and 12 weeks after starting and with any dose elevation and periodically

Fibric Acid Derivatives

Decrease Triglycerides (35-50%) Reduced hepatic secretion of VLDL through activation of PPAR-alpha receptors in liver Stimulate lipoprotein lipase and thus clearance of TG-rich lipoproteins Raise HDL (15-25%) Direct stimulation of HDL apolipoprotein synthesis A-I,II Increased transfer of apo A-I with diminished cholesterol transfer from HDL to VLDL Increases LDL buoyancy May also improve endothelial function and favorable effect on macrophage responses (possible reduction in CHD risk independent of effect on lipoproteins) Agents Gemfibrozil- 600 mg po BID (11% raise in HDL). Modest LDL reduction but little effect in combined hyperlipidemia. Can increase LDL in pure hypertriglyderidemia Fenofibrate 200 mg capsules or iii caps 67 mg qd (renal dosing and can decrease Cyclosporin levels). Better for LDL lowering Side effects Gallstone formation Dyspepsia, diarrhea, nausea, vomiting, abdominal pain, eczema, rash, vertigo and myalgias Adverse drug interaction Gemfibrozil- inhibits glucuronidation of lipophilic statins and increases levels thus increasde risk of myopathy. Also decreases warfarin by 30%

Nicotinic Acid

Mechanism of Action Inhibits hepatic VLDL production and its metabolite LDL Raises HDL by reducing lipid transfer of cholesterol from HDL to VLDL and by delaying HDL clearance Increase in LDL size Reduction in plasma fibrinogen levels Formulations and dosing Immediate release (crystalline): 100 TID and titrated to tolerance Sustained release Niacor Niaspan: 500 mg qhs x one month and then titrated to 1000 mg usually given daily after evenng meal Side effects Flushing (less common with controlled release) minimized with ASA 30 minutes before and limited in 7-10 days Nausea, paresthesias, pruritis (20% each) Elevation of hepatocellular enzymes and possible hepatotoxicity, jaundice and fulminant hepatitis (generally less common with Niaspan and crystalline niacin) Insulin resistance and worsening hyperglycemia (less with crystalline Niaspan) Hyperuricemia (AVOID IF H/O GOUT) Hypotension in combination with other vasodialtors (can increase unstable angina)


Ezetimibe
Mechanism: impairs dietary and biliary cholesterol absorption at the brush border of the intestines without affecting TG or fat-soluble vitamins possible Niemann-Pick C1 like protein involved in cholesterol transport LDL decrease 15-20% Trivial effects on HDL and TG Also adjunctive therapy to statins but same effect with higher dose of statin as in one study 10 zettia and 10 atorvastatin same effect as 80 atorvastatin Indications Avoiding high doses of statins Very high LDL (FCH) not sufficiently controlled on statins Adverse effects Only 20% absorption so lower side-effect profile Higher incidence of myopathy and elevated transaminases when coadministered with a statin

Bile Acid Sequestrants

Lower LDL (10-15%) BINDING BILE ACIDS IN INTESTINE CAUSING A DECLINE IN HEPATIC CHOLESTEROL POOL; THUS SYNTHESIS OF apo B/E (LDL) RECEPTORS Max doses cause 30% reduction Raise HDL Intestinal formation of nascent HDL Available agents Cholestyramine 8 grams/day. 24-30 grams/day can lower LDL up to 24% Colestipol 10 grams/day Colesevelam 1.5-4.5 grams/d Adverse effects Usually limit use Mainly GI (nausea, bloating, cramping)- least problematic with colesevelam Increased liver enzymes Also drug interactions (impair absorption) Digoxin, warfarin, and fat soluble vitamins (give one hour before or 4 hours after bile acid sequestrant) Contraindications: pts with elevated TG