Pharmacology - An Illustrated Review

25. Antihyperlipidemic Drugs

25.1 Lipids and Lipoproteins

Lipids (fats) are polar molecules made up of glycerol and fatty acids. Most dietary fats are triglycerides, which are made up of glycerol and three fatty acids. These are stored by the body and provide an energy source when required. Cholesterol is also ingested in smaller amounts. Cholesterol is an essential component of cell membranes. All lipids are insoluble in water and need to be coated in phospholipids, which contain apolipoproteins, to be absorbed in the circulation. These transport forms of lipids are designated as chylomicrons, low-density lipoproteins (LDLs), very-low-density lipoproteins (VLDLs), or high-density lipoproteins (HDLs), depending on their relative quantities of triglycerides and cholesterol, as well as the type of apolipoproteins in the phospholipid layer. Lipoprotein metabolism is shown in Fig. 25.1.

Lipoprotein levels

The optimal level for LDL cholesterol is < 100 mg/dL. It is considered high when it is ≥ 160 mg/dL. HDL cholesterol should ideally be < 40 mg/dL. It is considered high if it is > 60 mg/dL. Total cholesterol should be < 200 mg/dL. It is considered high if it is > 240 mg/dL.


Dyslipidemia and Related Diseases

Dyslipidemia is a general term used to describe high levels of LDL cholesterol (LDL-C) or triglycerides, or low levels of HDL cholesterol (HDL-C). Dyslipidemias are major contributors to atherosclerosis and atherosclerosis-related conditions, such as coronary heart disease (CHD), ischemic cerebrovascular disease, and peripheral vascular disease. Genetic disorders and life-style may contribute to the dyslipidemias. Therapy for dyslipidemias is based on the blood levels of LDL-C, HDL-C, and triglycerides (found mainly in VLDL cholesterol).

Fig. 25.1 image Lipoprotein metabolism.

Enterocytes release absorbed lipids in the form of triglyceride-rich chylomicrons. These are acted upon by lipoprotein lipases in endothelial cells, producing fatty acids, which are stored in tissues. The remnants of chylomicrons are transported to liver cells, where they are a source of dietary cholesterol. The liver uses this and hepatically produced cholesterol to synthesize very-low-density lipoproteins (VLDLs) and bile acids. VLDLs are released into the blood and supply tissues with fatty acids. The low-density lipoprotein (LDL) remnants either return to the liver or supply cells with cholesterol. (HDL, high-density lipoprotein.)


Antihyperlipidemic Therapy

Initial therapy is to institute lifestyle changes, including reduction of dietary intake of cholesterol and saturated fats and increased intake of soluble fiber and plant sterols. In addition, weight management and increased physical activity should be initiated. If these are insufficient to lower LDL-C to the desired level, drug therapy is indicated.

The National Cholesterol Education Program has established guidelines for initiation of drug therapy in dyslipidemias based on the blood levels of the lipoproteins after an overnight fast. The presence of other major risk factors, such as cigarette smoking, hypertension, low HDL-C (< 40 mg/dL), family history of premature CHD, and age, determine the level to which cholesterol should be lowered.

Role of genetics in hyperlipidemic diseases

Genetic defects in the production of chylomicrons, lipoprotein lipase, the synthesis of LDL receptors, and overproduction of the lipids/lipoproteins can be familial causes for hyperlipidemic diseases.


25.2 Antihyperlipidemic Drugs

Antihyperlipidemic drugs are used to treat hyperlipidemias or hyperlipoproteinemias and conditions characterized by elevated plasma levels of cholesterol or triglycerides, for example, type 2 diabetes, metabolic syndrome, and hypertriglyceridemia. Diabetics usually have high tri glycerides, moderate elevations of total cholesterol and LDL-C, and low HDL-C.

Metabolic syndrome

Metabolic syndrome is a combination of medical disorders that increases the risk of developing atherosclerotic disease, for example, coronary heart disease, peripheral vascular disease, and stroke. It also increases the risk of developing type 2 diabetes. Its etiology is unknown, but weight, advancing age, lifestyle factors, and genetics are all known to be involved. Signs of metabolic syndrome include fasting hyperglycemia, hypertension, abdominal obesity, high levels of triglycerides, and low levels of HDL-C. Treatment primarily involves weight management and increasing exercise, then drug management for hypertension, diabetes, and to correct lipid levels as appropriate.



The statins (3-hydroxy-3-methylglutaryl [HMG]−coenzyme A [CoA] inhibitors) have become the most widely prescribed drugs for lowering plasma cholesterol levels.

Atorvastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin, and Simvastatin

Mechanism of action. The major mechanism of these agents is to competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis (Fig. 25.2). This causes significant reductions in LDL-C by causing an increased expression of LDL receptors on hepatocytes and increased removal of LDL from the blood (Fig. 25.3). Statins also reduce blood triglyceride levels.


– Lowers LDL and triglyceride levels

– Increases HDL levels


– First-line treatment for hypercholesterolemia

– Used prophylactically to prevent adverse vascular events in patients with diabetes mellitus or cardiovascular disease

Side effects. These include gastrointestinal (GI) upset in < 10% of patients, muscle weakness in combination with fibrates, and altered liver enzymes.


– Liver disease

Drug Interactions. The HMG-CoA reductase inhibitors increase warfarin levels so prothrombin times (expressed as International Normalized Ratio [INR, see page 288]) should be monitored.

Fig. 25.2 image Accumulation and effect of HMG-CoA reductase inhibitors in the liver.

The HMG-CoA reductase inhibitors mimic the normal enzyme substrate, which renders it unavailable for cholesterol synthesis in the liver. These drugs accumulate in the liver, as they have a high rate of presystemic elimination. This accumulation is advantageous because it concentrates the actions of these drugs where they are needed. The liver maintains its requirement for cholesterol by the uptake of LDL from the blood, thus lowering plasma cholesterol levels.


Fig. 25.3 image Regulation by cellular cholesterol concentration of HMG-CoA reductase and LDL receptors.

In the presence of HMG-CoA reductase inhibitors, hepatocytes increase the production of LDL-receptor proteins. This allows LDL uptake from the blood to increase to provide the liver with its only source of cholesterol.



Rhabdomyolysis is the rapid breakdown of skeletal muscle due to injury to muscle tissue. The muscle breakdown product, myoglobin, is harmful to the kidney and can precipitate acute kidney failure. Signs and symptoms include pain, tenderness, and swelling of the affected muscle, as well as nausea, vomiting, confusion, arrhythmias, coma, anuria, and later disseminated intravascular coagulation (DIC). This is a rare complication of treatment with statins and fibrates.


Bile Acid Sequestrants

Cholestyramine and Colestipol

Mechanism of action. These agents are insoluble resins that are not absorbed by the body, but that bind bile acids in the gut, thus preventing bile acids from being absorbed. This necessitates an increase in the hepatic conversion of cholesterol to bile acids, thereby reducing the cholesterol available through the enterohepatic circulation for production of plasma lipids. They also lower LDL and plasma cholesterol. Figure 25.4 illustrates the effect of cholesterol-lowering drugs like cholestyramine on cholesterol metabolism in the liver.

Pharmacokinetics. Given orally, these drugs bind with bile acids in the intestine and produce an insoluble complex that is excreted in the feces.


– Decreases LDL levels

– May increase triglycerides, or they may remain unchanged

– Increases HDL levels

Uses. These agents are used alone for the treatment of hypercholesterolemia in patients 11 to 20 years of age. However, they are most often used as secondary agents if statin therapy does not reach its desired goal.

Side effects

– Nausea, constipation, steatorrhea (the presence of excess fat in feces), and deficiency of fat-soluble vitamins (A, D, E, K)

Note: Compliance may be a problem due to the unpleasant taste of the drug.

Drug interactions. These agents may interfere with the absorption of other drugs given concurrently (e.g., warfarin); therefore, drugs should be taken ~1 to 2 hours before or several hours after taking bile acid sequestrants.

Fig. 25.4 image Cholesterol metabolism in liver cell and cholesterol-lowering drugs.

Cholesterol-lowering drugs may act in the gut to reduce the absorption of dietary cholesterol, they may inhibit cholesterol synthesis in the liver, or they may act to increase the consumption of cholesterol.



Mechanism of action. Ezetimibe inhibits cholesterol absorption in the small intestine.


– Lowers LDL-C levels by ~18%

Uses. It is used primarily as adjunctive therapy with statins.

Side effects

– May increase the hepatotoxicity and myopathy of statins

Nicotinic Acid (Niacin)


Mechanisms of action

– Inhibition of hepatocyte diacylglycerol acyltransferase-2, a key enzyme for triacylglycerol synthesis, decreasing secretion of VLDL and LDL-C

– Decreased hepatic catabolism of apolipoprotein A-I increases the half-life and concentrations of HDL-C.

– Niacin also reduces vascular inflammatory genes involved in atherosclerosis.


– Decreases levels of LDL and triglycerides

– Increases HDL levels

Uses. Niacin is used to treat hypertriglyceridemias and hypercholesterolemia. It is especially useful in patients with both hypertriglyceridemia and low HDL-C levels.

Note: Nicotinamide is not effective in lowering lipids, although it acts interchangeably with nicotinic acid as a vitamin.

Side effects

– Cutaneous flushing, burning, and itching are common, as is GI irritation, nausea, and vomiting. The niacin flush results from the stimulation of prostaglandins D2 and E2 from subcutaneous Langerhans cells by a G protein–coupled niacin receptor.

– Activation of peptic ulcers, abnormal elevation of liver enzyme levels, hyperglycemia, and hyperuricemia occur infrequently.


– Chronic liver disease

– Gout (see page 359)

– May be inappropriate for use in peptic ulcer disease, hyperuricemia, and diabetes


Gemfibrozil and Clofibrate

Mechanism of action. These drugs lower VLDLs and plasma triglycerides by stimulating lipoprotein lipase. They also lower cholesterol by inhibiting its synthesis and enhancing excretion in the bile.


– Decreases LDL and triglyceride levels

– Increases HDL levels


– Hypertriglyceridemia and hypercholesterolemia

Side effects. Side effects include GI disturbances (nausea, diarrhea, and cramps), muscle weakness, and rash. Long-term use may increase the incidence of thromboembolism, angina, arrhythmias, or gallstones (see page 159).


– Pregnancy

– Impaired renal or hepatic function

Drug interactions. These agents displace acidic drugs (e.g., warfarin and phenytoin) from plasma proteins; thus a reduced dose of anticoagulant (or other drug) is required.