Understanding Coronary Heart Disease and Lipoproteins

• Coronary heart disease (CHD) accounts for around half of all deaths in the US
• CHD incidence correlates with elevated levels of LDL cholesterol and triacylglycerols, as well as low HDL cholesterol
• Other CHD risk factors: smoking, hypertension, obesity, and diabetes
• Elevated cholesterol can stem from lifestyle choices like lack of exercise or diets high in saturated fats
• Hyperlipidemias can result from single gene defects in lipoprotein metabolism, or more commonly, a mix of genetics and lifestyle
• Lifestyle changes and drug therapy can slow coronary plaque progression, regress existing lesions, and cut CHD mortality by 30–40%
• Antihyperlipidemic drugs should be taken continuously, as lipid levels return to pretreatment levels upon cessation
• Plasma lipids mainly comprise lipoproteins, which are spherical complexes of lipids and apolipoproteins
• Clinically significant lipoproteins (in decreasing order of atherogenicity): LDL, VLDL and chylomicrons, and HDL
• High total cholesterol, especially elevated LDL, is positively linked to CHD
• High HDL cholesterol has been linked with decreased heart disease risk
• Lowering LDL is the main focus of cholesterol-lowering therapy
• LDL cholesterol reduction goals depend on CHD coexistence and cardiac risk factors
• Higher heart disease risk warrants more aggressive LDL-lowering treatment

Hypercholesterolemia Treatment

• Lifestyle changes like diet, exercise, and weight loss can modestly decrease LDL and increase HDL in moderate hyperlipidemia
• Many patients need drug therapy to reach LDL goals
• Drug therapy candidates include patients with LDL levels over 160 mg/dL and one major risk factor like hypertension, diabetes, smoking, or a family history of early CHD
• Patients with two or more additional risk factors should aggressively aim for LDL levels below 100 mg/dL, or even 70 mg/dL in some cases

Hypertriacylglycerolemia Treatment

• Elevated triacylglycerol (triglyceride) levels are tied to increased CHD risk
• Diet and exercise are primary treatments for this condition
• Niacin and fibric acid derivatives are effective at lowering triacylglycerol levels if needed
• Statin drugs offer a secondary benefit of triacylglycerol reduction (primary benefit: LDL cholesterol reduction)
• VLDL is mainly composed of triacylglycerol

Drugs Lowering Serum Lipoprotein Concentration

• Antihyperlipidemic drugs address elevated serum lipids through various strategies.
• Some reduce production of lipoprotein carriers for cholesterol and triglyceride.
• Others boost lipoprotein degradation, decrease cholesterol absorption, or increase cholesterol removal from the body.
• Use includes dietary saturated and trans fat restriction and calorie control

HMG CoA Reductase Inhibitors (Statins)

• Statins lower elevated LDL cholesterol, leading to reduced coronary events and death
• This class of drugs inhibits an early step of cholesterol synthesis
• They are first-line for patients with high LDL cholesterol
• Benefits can include plaque stabilization, improved coronary endothelial function, inhibited platelet thrombus formation, and reduced inflammation
• The value of cholesterol lowering with statins is demonstrated in patients:
• Those with or without hyperlipidemia, men with hyperlipidemia but no CHD, and men and women with average total and LDL cholesterol levels and no known CHD

Statin Mechanism of Action

• analogs compete to inhibit HMG CoA reductase, the rate-limiting step in cholesterol synthesis.
• This depletes the intracellular cholesterol supply
• Pitavastatin, rosuvastatin, and atorvastatin most potent LDL cholesterol-lowering statins, followed by simvastatin, pravastatin, then lovastatin and fluvastatin
• Reduced intracellular cholesterol stimulates LDL receptor synthesis
• This promotes LDL uptake from the blood
• Lastly, decreased secretion of VLDL