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Hyperlipidemia Treatment

On a general basis, for every 1% reduction in LDL, there is a 1% reduction in the rate of having CHD events (1). A 1% elevation of HDL results in approximately 2% reduction of experiencing CHD events (1).

Statin

Statins are usually the first choice of therapy as there are the most potent agents at lowering LDL (1,2). They inhibit the conversion of HMG-CoA to mevalonate, which is the rate limiting step in the de novo biosynthesis of cholesterol (1,2,5). This is done by inhibiting HMG-CoA reductase (1,2,5). The CURVES study, which is the largest head to head comparision of statins showed that atorvastatin was the most potent drug at lowering the LDL-C and total cholesterol (5). The reductions in LDL-C were 38%, 46%, 51%, and 54% for the 10, 20, 40, 80 mg doses respectively (5). Statins are also proven to reduce the risk of CHD, stroke and CV death (1,2,4). The data regarding the efficacy and safety of statins goes back nearly 25 years (1). These drugs are effective in reducing MIs, strokes, revascularization procedures and total mortality in some circumstances (1,2,4). This has been validated in both genders, the elderly, in patients with hypertension and with preexisting CHD (1,2,4). Statins lower LDL-C levels by approximately 25-62% depending on the statin used (1,2). Each doubling of the daily dose produces an additional 6% average reduction for statins (2). Statins are also effective at reducing triglycerides and they can raise HDL cholesterol to a certain extent (2). The synthesis of L-mevalonic acid is inhibited by statins, which further inhibits other products that may affect gene transcription and intracellular transport (1,2). This is a possible explanation for the cholesterol independent effects, which include thrombosis inhibition, and decreases in lipoprotein oxidation (1,2). Statins are well tolerated (5). Less than 4% of the patients discontinue statins due to adverse effects in clinical trials (1,5). Statins may cause an elevation in liver function tests and may cause rhabdomyolysis and myopathy (1,5). LFT elevations that are more than 3 times the normal upper limit may signify liver toxicity, and thus LFT should be obtained at baseline, and 6 to 12 weeks after starting therapy or after any dose escalation and then yearly (4). Rhabdomyolysis is defined as the elevation in CK that is 10 times the upper limit of the normal (1,2). Concomitant gemfibrozil use with statins should be avoided as the risk of rhabdomyolysis is increased (1,2). Baseline CK measurements should be obtained prior towards starting therapy (1,4). Prior CK measurements should only be taken if patients are symptomatic, otherwise routine monitoring is of no value (1,2,4). Most statins except pravstatin are metabolized by hepatically by the CYP P450 enzymes (5). Because of this, statins should be avoided with CYP3A4 inhibitors, such as macrolide antibiotics, gemfibrozil, grapefruit juice, azoles, protease inhibitors and nondihydropyridine calcium channel blockers such as verapamil (5). Initial changes in the lipid profile are seen in 3-5 days and the max effect on the lipids generally takes 4 to 6 weeks (1). The majority of the statins are eliminated through bile and urine (1). Statins are contraindicated in active liver disease, and high alcohol consumption (5). It is also cautioned in patients with moderate to severe renal impairment (<60 mL/min) (5).

Ezetimibe

Ezetimibe is a cholesterol absorption inhibitor at the brush border of the intestines (1,2). It exerts its effects by binding to the NPC1L1 transporter (1,2). This reduces the delivery of cholesterol to the liver and thus reduces the cholesterol stores inside the liver (1). This drug causes an average of 54% inhibition of the intestinal cholesterol absorption (1). Since the liver cholesterol stores are reduced, there is an up-regulation of LDL receptors that will also decrease serum cholesterol (1). The LDL cholesterol is reduced by an average of 18% (1). Triglycerides are reduced by 7% to 9% and a modest increase in HDL cholesterol is observed (1). The time for max effect on lipids is about 2 weeks (1). The major route of excretion for ezetimibe is through the feces and less extensively through the urine (6). This drug is metabolized in the small intestine and the liver (6). This medication is well tolerated; some side effects may include dizziness, diarrhea, and abdominal pain (5). Ezetimibe is contraindicated in severe hepatic impairment (5). There is low potential for drug interactions with ezetimibe; however, cyclosporine may increase ezetimibe concentrations (5). Bile acid sequestrants may decrease absorption of ezetimibe (5). If used with a fenofibrate, LFTs and signs and symptoms of cholelithiasis should be monitored (5).

Bile Acid Sequestrants (Cholestyramine, colestipol)

This are highly charged molecules that bind to the bile acids in the gut (1,2). The corresponding resin-bile acid complex cannot be absorbed and is excreted into the feces (1,2). The loss of the bile causes a compensatory mechanism in which the hepatic cholesterol is made into bile, which reduces the stores in the liver and there is also an up regulation of LDL receptors to decrease the serum LDL concentrations (1,2). Studies have illustrated that resins can reduce CHD events in patients that do not have CHD (4). They also reduce LDL from 15% to 30% and increase HDL cholesterol 3% to 5% (1,2). Since these drugs are not absorbed, the adverse effects are localized in the GI tract. 20% of patients taking either of these bile acid sequestrants have noted constipation, flatulence and boating (1,2). A large number of patients discontinue therapy due to these symptoms (1,2). Lowest dose should be taken and then escalated slowly as tolerated (5). These resins can prevent the absorption of drugs such as digoxin, warfarin, thiazides, beta blockers, folic acid and fat soluble vitamins (5). These interactions can be reduced by taking the resin 1 hour before or 4 hours after these agents (5). The time until max effect on the lipids is generally 2 to 4 weeks (1). This medication is contraindicated in biliary obstruction, when TG > 4.6 mmol/L and phenylketonurics (5).

Niacin

Niacin is indicated for patients that have high levels of triglycerides, low HDL cholesterol and elevated levels of LDL cholesterol (1,2). It inhibits the fatty acid release from adipose tissue, and inhibits the production of trigylcerides and fatty acids in liver cells (1,2). This will result in increased intracellular degradation of apolipoprotein B, which will reduce the number of VLDL particles secreted (1,2). The uptake of HDL apolipoprotein A1 particles is also reduced (1,2). The VLDL and LDL lowering effects are achieved once a daily dose of 1.5-2.0 grams are taken (1,2). Nicotinic acid causes hot flushes, pruritus, dry skin and may cause severe hepatotoxicity (more common with slow release formulation) (5). Niacin can reduce LDL from 5% to 25%, trigylcerides by 20% to 50% and increase HDL by 15% to 35% (1). It has also been shown to reduce CHD events and total mortality (4). The max effect on lipids for niacins is generally 3 to 5 weeks (1). Caution should be advised if niacin is used with statins as there is a potential increase of hepatotoxicity and myopathy (1). Uric acid levels may be elevated and these should be monitored at 3 months, 6 months, and 12 months, then yearly (5). This medication is contraindicated in severe PUD, severe gout and hepatic disease (5). Niacin is metabolized by the liver and there is first pass metabolism present (6). It is excreted in urine (6).

Fibrates

Fibrates decrease triglyceride levels by 20% to 50% and increase HDL cholesterol by 9% to 30% (1,2). The effect of fibrates on LDL is variable; and may even increase in patients that have high triglycerides (1,2). Fibrates bind to PPAR-alpha receptor, which reduces apolipoproteins B, C-III, and E, and increases apolipoproteins A-I and A-II (1). The overall changes in the apolipoporteins cause a reduction in VLDL, IDL and increase in HDL (1). This class of medication is well tolerated (5). The most common adverse effects include abdominal pain, diarrhea, flatulence, rash and dyspepsia (5). Myopathy and rhabdomyolysis may occur, and increases in risk of renal insufficiency or concurrent statin therapy is taken (5). If a fibrate is used with a statin, fenofibrate is the preferred medication because it inhibits the glucoronidation of the statin hydroxyl and moiety less than gemfibrozil, which allows greater renal clearance of the statins (5). Patients who begin fibrate therapy should have the CK levels checked prior to starting therapy and again if the patient is symptomatic (5). Liver dysfunction has been noted and the LFTS should also be monitored (5). Fibrates may increase the cholesterol in the bile; choleithiasis and cholecystitis may occur (5). This medication is contraindicated in hepatic impairment, renal dysfunction and if pre existing gallbladder disease is present (1). The max effect on lipids is generally 2 weeks for fenofibrate and 3 to 4 weeks for gemfibrozil (1,6). This drug class is metabolized by the liver and is cleared in the urine (primarily) and the feces (6).

Non Pharmacological Treatment

Dietary interventions include decreasing the cholesterol intake to <200 mg/day (1,2,4). Fat intake should be restricted to 20% of calories and less than 7% of daily calories as saturated fat and trans fatty acids (1,2,4).. Omega 3 fatty acids should be increased and this can come from fish and plant sources (1,2,4).. High fibre intake should be favored (1,2,4).. Alcohol consumption should be limited to 5% of total calories (1,2,4).. Sunflower, safflower, soybean, canola, corn, or olive oil should be used instead of palm or coconut oils (1,2,4).. Lean cuts of meat should be chosen (1,2,4).. White meat should be preferred over red meat because there is less cholesterol (1,2,4).. Vegetable intake should be increased (1,2,4).. Patients should get at least 20 to 30 minutes of aerobic exercise every other day (1,2,4)..

References

  1. Chisholm-Burns MA, Wells BG, Schwinghammer TL, Malone PM, Kolesar JM, Rotschafer JC, Dipiro JT. Pharmacotherapy: Principles and Practice. McGraw-Hill: 2008. p. 385
  2. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2007. p. 175
  3. Jones P, Kafonek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998;81(5):582.
  4. Zhai XQ, Hodgson, JM, Schlever AM. Hyperlipidemia. MD Consult [online]. Maryland Heights MO: Elsevier Inc. 2011 [cited 2011 Nov 6]. Available from: www.mdconsult.com
  5. Repchinsky C, editor-in-chief. Therapeutic Choices. 6th ed. Canadian Pharmacists Association; 2011. p. 432.
  6. Ezetimibe, niacin, gemfibrozil, fenofibrate. In: Drug Monographs [online]. McGraw-Hill’s Access Medicine; No date [cited 2011 Nov 6]. Available from: http://www.accessmedicine.com/

Disclaimer

This information is presented for informational purposes only and is not meant to be a substitute for advice provided by qualified health care professionals. You should contact your qualified health care provider if you have or suspect any health problems. This article is not intended to provide medical advice for its readers


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