Lipoprotein management in Patients With Cardiometabolic

Risk Consensus conference report JACC April

2008

Sandra Rodriguez, M.D.

Internal Medicine

Factors Contribuiting to Cardiometabolic risk

To What Extent Do Lipoproteins Contribute to CVD?

• Serum levels of lipids and lipoprotein lipids have proven to be among the most potent and best substantiated risk factors for atherosclerosis in general and coronary heart disease (CHD) in particular.

• Lipoproteins, as LDL, interact with the arterial wall, in the intima the LDL bound to proteoglycans, where it suffers oxidation, macrophage uptake and foam cell formation, initiating the cascade of atherosclerosis.

• Small VLDL’s and IDL’s can enter the subendothelial space also, and they increase prothrombotic factors.

• Small dense LDL have increase endothelial permeability.• HDL is inversely associated to CV risk.

What Are the Clinically Important Lipoprotein Parameters?

• LDL Cholesterol: Lowers CVD event rates for primary and secondary prevention. (HPS, CARDS, SSSS). Measurement might be underestimated as triglycerides levels increase.

• LDL Particle number and size: Both are important predictors of CVD. Found strongly associate to Carotid intima-media thickness (MESA) and CHD events(VA-HIT). Not widely available, and is expensive.

• Lp(a): Is an apoB-LDL, predicts CVD, if high, more aggressive treatment is recommended.

What Are the Clinically Important Lipoprotein Parameters?

• Non-HDL Cholesterol: Is a secondary goal after LDL. Became better predictor of CVR in statin-treated patients. Can be nonfasting.

• ApoB-100: Represents total atherogenic particles, nonfasting. Better predictor of CVD risk than LDL, even more once the LDL is lowered. More value in patientes with cardiometabolic risk. Associated with obesity, diabetes, insulin resistance, and Non-HDL.

• Triglycerides: Univariate predictor of CVD but not independent.

• HDL: Strong inverse predictor of CVD events in diabetics and nondiabetics.

In the Evaluation and Treatment of Patients with Lipoprotein Abnormalities, Are There Other Factors That

Should Be Considered?

What Are the Principles and Objectives of Treatment of Lipoprotein Abnormalities?

• Lipoprotein Goals for Three Risk Levels:– RiskLevel/LDL/

NonHDL/ ApoB (mg/dl)

• CVD and CVD risk equivalent<70/100/80

• Multiple (2+) risk factors<100/130/90

• 0–1 risk factor<130/160• Triglycerides <150mg is

fourth goal except if initial more than 500mg/dl.

• Weight loss of 5-10%• Diet Cholesterol

<200mg/day• Saturated and trans

fat to <7% of calories.• Measure LDL, and

Non-HDL and ApoB in patients with CMR on statins.

Types of lipids• Cholesterol: essential component of cell

membranes, substrate for steroid hormones and bile acids.

• Cholesteryl esters: Circulating from of cholesterol, in the core of lipoprotein particles. The enzyme lecithin cholesterol acyltransferase (LCAT) forms cholesteryl esters in the blood compartment by transferring a fatty acyl chain from phosphatidylcholine to cholesterol.

• Triglycerides consist of a three-carbon glycerol backbone covalently linked to three fatty acids. Triglyceride molecules are nonpolar and hydrophobic; they are transported in the core of the lipoprotein. Hydrolysis of triglycerides by lipases generates free fatty acids (FFAs) used for energy.

• Phospholipids, constituents of all cellular membranes, consist of a glycerol molecule linked to two fatty acids, soluble than triglycerides or cholesterol or its esters. Hydrolysis by phospholipases generates second messengers such as diacyl glycerols, lysophospholipids, phosphatidic acids, and FFAs such as arachidonate that can regulate many cell functions.

Lipoproteins

Lipid Transport System

Lipoprotein Management

Current Lipid-Lowering Medications• Statins: Atorvastatin, Fluvastatin, Lovastatin,

Pravastatin, Rosuvastatin,Simvastatin.• Bile Acid Absorption Inhibitor

– CholestyramineQuestran 4-24 gm– Colestipol, Colestid5-30 gm– Colesevelam, WelChol3.8-4.5 gm

• Cholesterol Absorption Inhibitors:– Ezetimibe: Zetia10

• Fibrates: Lopid600-1200 mg• Niacin: Niacin1-3 gm, Nicotinic acid1-2 gm

Bile Acid–Binding Resins • Interrupt the enterohepatic circulation of bile acids by inhibiting their

reabsorption in the intestine (more than 90 percent of bile acids reabsorbed).

• Adjunctive therapy in patients with severe hypercholesterolemia due to increased LDL cholesterol.

• Because bile acid–binding resins are not absorbed systemically (they remain in the intestine and are eliminated in the stool), they are considered safe in children.

• Cholestyramine (Questran) is used in 4-gm unit doses as powder, and colestipol (Colestid) is used in 5-gm unit doses. Effective doses range from 2 to 6 unit doses/day, always taken with meals.

• Side effects: sensation of fullness, gastrointestinal discomfort. Hypertriglyceridemia can result from the use of these drugs. Decreased drug absorption.

• Can be used in combination with statins and/or cholesterol absorption inhibitors in cases of severe hypercholesterolemia.

Hydroxymethylglutaryl–Coenzyme A Reductase Inhibitors (Statins)

• Statins prevent the formation of mevalonate, the rate-limiting step of sterol synthesis. To maintain cellular cholesterol homeostasis, expression of the LDL-R increases and the rate of cholesteryl ester formation declines. These homeostatic adjustments to HMG-CoA reductase inhibition increase LDL cholesterol clearance from plasma and decrease hepatic production of VLDL and LDL.

• Statins may increase HDL cholesterol in part by regulating apo AI transcription.[49] Altered protein prenylation may also mediate some of the putative effects of statins not related to a reduction in LDL cholesterol levels.

• Statins decrease C-reactive protein, induce apoptosis in smooth muscle cells, alter collagen content of atherosclerotic plaques, alter endothelial function, and decrease the inflammatory component of plaques. Some investigators argue that statins possess effects independent of their inhibition of HMG CoA reductase.

• Side effects include reversible elevation in transaminases and myositis, in less than 1%. Concomitant drugs that interfere with the metabolism of statins by inhibiting the cytochrome P450 can increase plasma concentrations of statins. These include antibiotics, antifungal medications, certain antiviral drugs, grapefruit juice, cyclosporine, amiodarone, and several others.

Studies

• SSSS: 4444 patients w/ CHD, at 5.4yr showed 30-44% mortality and CHD events.

• West of Scotland Study: Pravastatin reduce CHD events by 32% and mortality by 22%.

• HPS: Simvastatin reduced risk of major CV events in 25%.• CARE: Pravastatin reduce CV event in 24% in patients with average

total cholesterol of 209mg/dl. • FIELD: Non-fatal MI decreased by 24%.• Helsinki Heart Study showed no decrease in total mortality.

Cholesterol Absorption Inhibitors

• Ezetimibe is the first such compound. It appears to limit selective uptake of cholesterol and other sterols by intestinal epithelial cells, by interfering with the Niemann-Pick C1-like 1 protein .

• Ezetimibe is indicated for patients with LDL cholesterol levels above target on a maximally tolerated statin dose.

• Ezetimibe lowers LDL cholesterol by about 18 percent and adds to the effect of statins.

• It might be the drug of choice in cases of sitosterolemia.

Fibric Acid Derivatives (Fibrates)

• For hypertriglyceridemia when diet and lifestyle changes are not

sufficient. Also prevention of cardiovascular diseases in patients with elevated plasma triglycerides and low HDL cholesterol, although the data supporting their use are weaker than those for statins.

• Side effects: cutaneous manifestations; Gl effects (abdominal discomfort, increased bile lithogenicity); erectile dysfunction; elevated transaminases; interaction with oral anticoagulants; and elevated plasma homocysteine, especially with fenofibrate and, to a lesser extent, with bezafibrate.

• Because fibrates increase LPL activity, LDL cholesterol levels may rise in patients with hypertriglyceridemia treated with this class of medications.

• Fibrates, especially gemfibrozil, can inhibit the glucuronidation of statins and thus retard their elimination. For this reason, combination of gemfibrozil with statins may increase the risk of myotoxicity.

Nicotinic Acid (Niacin) • Increases HDL cholesterol and lowering triglyceride levels. The effect of

niacin on LDL cholesterol is more modest.• Effective doses of niacin are in the range of 3000 mg/day, in three separate

doses. Using an escalating dose schedule to reach the full dose in 2 to 3 weeks rather than starting with the full dose is preferable.

• Slow-release forms of niacin including Niaspan (1 to 2 gm/day) decrease the side effect profile of the drug. Niacin decreases the hepatic secretion of VLDL from the liver and decreased FFA mobilization for the periphery.

• Side effects of niacin include flushing, hyperuricemia, hyperglycemia, hepatotoxicity, acanthosis nigricans, and gastritis. Close laboratory monitoring of side effects is warranted. Long-acting niacin has the advantage of a once- or twice-daily dosing schedule, but older preparations of slow-release niacin were potentially more hepatotoxic.

• Niacin effectively raises HDL cholesterol levels and, in combination with low-dose statin, can retard the angiographic progression of CAD and decrease adverse cardiac events.

Other

• Fish oils are rich in polyunsaturated fatty acids such as eicosapentaenoic acid or docosahexaenoic acid, with the first double bond in the omega-3 position.

• These fatty acids lower plasma triglyceride levels and have antithrombotic properties at doses >4g/day and as adyuvant to statin can lower non-HDL cholesterol.

• Fish oils decrease VLDL synthesis and decrease VLDL apo B.

• Metformin has modest triglyceride lowering properties.• Pioglitazone raises HDL and lowers triglycerides and

LDL.• Rosiglitazone increases LDL particle number.

Algorithm for lipid lowering therapy