Case: Lipid-lowering agents. Discusssion
Class
Drugs that decrease plasma lipids are among the most commonly prescribed today. Some of these affect primarily cholesterol (e.g., the statins) and are useful in the treatment of hypercholesterolemia while other agents affect primarily triglycerides (e.g., gemfibrozil).
The National Cholesterol Education Program (NCEP) has classified levels of plasma cholesterol (Table National Cholesterol Education Program (NCEP) Levels of Plasma Cholesterol). The LDL cholesterol treatment goal is determined by assessing the risk of cardiovascular disease of individual patients. The major risk factors that modify LDL goals are listed in Table Risk factors for cardiovascular disease.
Table: National Cholesterol Education Program (NCEP) Levels of Plasma Cholesterol
| LDL cholesterol (mg/dL) | Categorization |
| <100 | Optimal |
| 100-129 | Near/above optimal |
| 130-139 | Borderline high |
| 160-189 | High |
| >190 | Very high |
| Total cholesterol (mg/dL) | |
| <200 | Desirable |
| 200-239 | Borderline high |
| >240 | High |
| HDL cholesterol (mg/dL) | |
| <40 | Low |
| >60 | High |
Table: Risk factors for cardiovascular disease
| Clinical CVD |
| Cigarette Smoking |
| Hypertension (BP > 140/90 mm Hg) or on an antihypertensive drug |
| Low HDL cholesterol (<40 mg/dL) |
| Family history of premature coronary heart disease |
| Age (men >45 years, women >55 years) |
| Poor nutrition |
Known CHD include patients who have had an infarction or angina or a surgical procedure for cardiovascular disease. In addition, patients with peripheral arterial disease, abdominal aortic aneurism, or symptomatic carotid artery disease or diabetes are considered to have known CHD or a high risk for CHD. The NCEP classification and the risk assessment are combined and used to modify the LDL cholesterol goals as illustrated in Table Cardiovascular risk and LDL GoAL.
Table: Cardiovascular risk and LDL GoAL
| Risk level | LDL GoAL (mg/dL) |
| Known CHD | <100 |
| > 2 risk factors | <130 |
| 0-1 risk factors | <160 |
Agents Used for Hypercholesterolemia
Statins
Of the drugs that decrease plasma cholesterol, the statins have gained the widest use. The statins are structural analogs of the substrate HMG-CoA that inhibit the activity of the enzyme HMG-CoA reductase at nanomolar concentrations. This enzyme is required for the synthesis of isoprenoids and cholesterol. By inhibiting de novo biosynthesis of cholesterol, cellular uptake of cholesterol from plasma via the LDL receptor is increased, reducing plasma cholesterol levels. Because statins have additional actions to inhibit the production of the triglyceride-rich VLDL, this makes them useful in the management of patients with hypertriglyceridemia; atorvastatin and rosuvas-tatin are particularly effective in this regard. There is evidence that statins also have anti-inflammatory activity, and this may contribute to their reduction in cardiovascular events. Statins may also reduce the rate of bone resorption and thereby lessen osteoporosis. This effect is thought to be caused by the inhibition of isoprenoid biosynthesis in osteoclast precursors, which inhibits their differentiation into mature osteoclasts. Six statins are approved in the United States: lovastatin, rosuvastatin, fluvastatin, atorvastatin, pravas-tatin, and simvastatin. They differ in efficacy: Rosuvastatin has been reported to reduce LDL cholesterol by more than 60 percent; atorvastatin, approximately 50 percent; and pravastatin and fluvastatin, approximately 35 percent. All of the statins are active orally. Lovastatin and simvastatin are prodrugs that are converted to their active metabolite by the liver.
The two major adverse effects associated with statin use are hepato-toxicity and myopathy. Hepatotoxicity was initially thought to be as high as 1 percent with elevations in hepatic transaminases as high as three times the upper limits. Subsequent clinical trials indicate that the actual incidence of hepatotoxicity is much lower. Hepatic transaminase levels should be monitored on initiation of therapy and at least yearly thereafter. The myopathy associated with statin use occurs in less than 0.1 percent of patients. However, severe rhabdomyolysis has occurred rarely, and one statin, cerivastatin, was removed from the market after several rhabdomyolysis-associated deaths.
Bile-Acid-Binding Resins
The bile acid sequestrants are also useful in reducing plasma cholesterol. Cholestyramine, colestipol, and colesevelam are ion-exchange resins that nonspecifically bind bile acids within the intestine and thereby reduce their enterohepatic circulation. This increases de novo hepatic bile acid synthesis and the cholesterol for this synthesis comes, in part, from the plasma via the LDL receptor. Bile acid sequestrants typically reduce plasma cholesterol by 15-20 percent with no effect on triglycerides. Because they are not absorbed, the bile acid sequestrants are quite safe, and adverse effects are typically gastrointestinal and include bloating and constipation. In the intestine, these agents bind many molecules other than bile acids and they impair the absorption of lipid-soluble vitamins and many drugs including digoxin, furosemide, thiazides, coumarin, and some statins. Patient adherence with these drugs is poor.
Inhibitors of Cholesterol Absorption
Ezetimibe is a new class of cholesterol-lowering drug that acts within the intestine to reduce cholesterol absorption. Cholesterol is absorbed from the small intestine by a process that includes specific transporters that have not been completely characterized. Ezetimibe appears to block one or more of these cholesterol transporters, thereby reducing cholesterol absorption. Ezetimibe used alone produces a reduction in plasma cholesterol of approximately 19 percent and an approximate 10 percent decline in triglyceride levels. When combined with a statin, reductions in plasma cholesterol as high as 72 percent have been reported in clinical trials. The complementary mechanisms — inhibition of cholesterol biosynthesis by statins and inhibition of cholesterol absorption by ezetimibe — may be useful in treating patients with refractory hypercholesterolemia. Few adverse effects have been reported with ezetimibe, but clinical experience is limited. The most frequently reported adverse effects are back and joint pain.
Nicotinic Acid
Niacin, at doses well beyond those used as a vitamin, has effects on all plasma lipids. It reduces LDL cholesterol by 20-30 percent and reduces triglycerides by 35-45 percent. It is the best agent available for increasing HDL. Niacin inhibits VLDL production in the liver by inhibiting both the synthesis and esterification of fatty acids. LDL levels are reduced as a consequence of the decline in VLDL synthesis. Niacin inhibits lipolysis in adipose tissue which reduces the supply of fatty acids to the liver, further decreasing VLDL synthesis. HDL levels are increased because niacin decreases the catabohsm of Apo A1 Niacin is useful in treating hypertriglyceridemia as well as hypercholesterolemia especially in the presence of low HDL. The limiting adverse effect of niacin is cutaneous flushing and itching, and dyspepsia is common at the doses (1 g/day) necessary to affect lipids. More medically serious adverse effects include hepatotoxicity and hyperglycemia. Niacin induces an insulin-resistant state causing hyperglycemia. For this reason niacin should not be used in diabetic patients.
Agents Used for Hypertriglyceridemia — Fibrates
The fibrates include clofibrate, fenofibrate, ciprofibrate, bezafibrate, and gemfibrozil. These agents predominantly cause a decline plasma triglycerides and a small decrease in LDL cholesterol. HDL levels are increased. The fibrates bind to a nuclear receptor peroxisomal proliferator-activator receptor Ύ (PPAR-Ύ) mostly in liver and skeletal muscle. Agonist-bound PPAR-Ύ induces lipoprotein lipase (LPL), which increases the lipolysis of triglyceride-rich VLDL and chylomicrons. Fibrates reduce triglycerides by 35-50 percent and LDL cholesterol by 10-20 percent. HDL levels are increased by 10-15 percent. All of the fibrates are orally active, but their absorption is decreased by food. The major adverse effect is gastrointestinal upset, cutaneous rash, and itching. Fibrates should not be used in patients with compromised renal function.
Case: Lipid-lowering agents. Questions – Answers
This post has been viewed 2619 times.
Comments are closed.
