Therapeutic Approaches to Atherosclerosis

Abstract

Therapeutic approaches
Prevention and treatment of atherosclerosis requires risk factor control, including the treatment of hypertension and diabetes mellitus, and lifestyle modification, i.e. diet, exercise and cessation of smoking. Established therapeutic approaches to atherosclerosis chiefly fall into two categories: lipid-lowering and anti-hypertensive therapies and include a number of drug categories, with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) being the most widely prescribed. The leading brands in the categories discussed are Lipitor, Plavix, Norvasc, Crestor. Zetia and Zocor1.

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Lipid-lowering therapies

Statin therapy
Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, which is involved in cholesterol synthesis, especially in the liver. In the short term, they decrease cholesterol and LDL, but over time this rises to baseline levels, However in long-term therapy, LDL levels remain low, which is believed to be due to an increase in the number of LDL receptors. Receptor density is an important factor in atherosclerosis, patients with familial hypercholesteremia may have less than half the normal level of LDL receptors, and statin therapy has proved effective in such cases2.

The effect of statins may extend beyond the regulation of lipid content. These actions, which include modification of endothelial function, plaque stability, and inflammatory pathways, are widely referred to as 'pleiotropic effects', and indicate that the therapeutic potential of statins might extend to other inflammatory disorders or conditions such as transplantation, multiple sclerosis, rheumatoid arthritis and chronic kidney disease3. Known actions include the following:

  • Plaque stabilization and decreased susceptibility to rupture by reducing cholesterol synthesis in macrophages, decreased inflammatory cells, decreased matrix metalloproteinase activation, and promotion of collagen accumulation in the fibrous cap4.
  • Reduction of the levels of C-reactive protein5.
  • Reduction of circulating concentrations of atherogenic apoB-containing lipoproteins by decrease of hepatic VLDL, and thus the production of LDL. Statins also increase the clearance of these particles through increasing numbers of LDL receptors in the liver6.
  • Decrease of smooth muscle cell growth has been demonstrated in vitro at pharmacological doses7.
  • Reduction of endothelial dysfunction8.
  • Inhibition of platelet reactivity and aggregation by modulating oxidised LDL9
  • Reduction in thrombus formation8.

Specifications for their use are as follows and are summarised in table 1:

Table 1: Statin Therapeutics and their Clinical Characteristics

Indications
Primary hypercholesteremia, patients who do not respond adequately to dietary control

Cautions
Should be used with caution in those with a history of liver disease or with high alcohol intake. Liver function tests should be carried out 1-3 months after treatment commences, and thereafter at 6 monthly intervals for a year, unless indicated sooner by signs or symptoms of hepatotoxicity. Treatment should be discontinued if serum transaminase concentration is elevated to 3 times the l upper normal limit. Consumption of grapefruit juice decreases metabolism of most statins, particularly atorvastatin, lovastatin and simvastatin10.

Contra-indications
Contra-indicated in active liver disease or abnormal liver function test results, and in pregnancy and breast feeding.

Side effects
Muscle effects: myalgia, myostitis and myopathy (<1%) have been reported. In rare cases myopathy can lead to acute rhabdomyolysis and irreversible renal failure11. If creatine kinase level is elevated beyond 10 times the upper normal limit, and myopathy is suspected, treatment should be discontinued. The risk of myopathy also increases if statins are given with the following:

  • fibrate
  • niacin
  • immunosuppressants such as cyclosporin

Other effects include headache (<5%), elevation of liver enzymes (1-2% patients), hepatitis rarely, gastro-intestinal effects including abdominal pain, flatulence, diarrhoea, nausea and vomiting (<5%). Rash and hypersensitivity reactions including angiodema and anaphylaxis are rare. It is generally considered that side effects are rare and far outweighed by the benefits12. Rosuvastatin and atorvastain are the most potent statins in terms of lowering LDL, followed by simvastatin and pravastatin. Differences in increasing HDL or decreasing triglycerides are less clear.

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