Treatment of Dyslipidemia

The most serious side effects are liver failure and rhabdomyolysis. Serious liver damage caused by statins is rare. More often, statins cause abnormalities of liver tests.

Abnormal tests usually return to normal even if a statin is continued, but if the abnormal test value is greater than three times the upper limit of normal, the statin usually is stopped. Liver tests should be measured before statins are started and if there is a medical concern about liver damage thereafter.

Statins have some important drug interactions. The first type of interaction involves the enzymes responsible for the elimination of statins by the liver. Liver enzymes (specifically, the cytochrome P-450 liver enzymes) are responsible for eliminating all statins from the body with the exception of pravastatin and rosuvastatin.

Therefore, drugs that block the action of these liver enzymes increase the levels of simvastatin, lovastatin, fluvastatin, and atorvastatin (but not pravastatin or rosuvastatin) in the blood and can lead to the development of rhabdomyolysis.

Rhabdomyolysis is a rare serious side effect which involves damage to muscles. Rhabdomyolysis often begins as muscle pain and can progress to loss of muscle cells, kidney failure, and death.

It occurs more often when statins are used in combination with other drugs that themselves cause rhabdomyolysis or with drugs that prevent the elimination of statins and raise the levels of statins in the blood. Since rhabdomyolysis may be fatal, unexplained joint or muscle pain that occurs while taking statins should be brought to the attention of a health care professional for evaluation.

Statins must not be used during pregnancy because of the risk of serious adverse effects to the developing fetus.

Another important drug interaction occurs between statins and niacin and fibric acids (forexample, gemfibrozil [Lopid], clofibrate [Atromid-S], andfenofibrate [Tricor]). Niacin and the fibric acid drugs can cause rhabdomyolysis or liver failure when used alone, and combining them with statins increases the likelihood of rhabdomyolysis or liver failure. Gemfibrozil should not be combined with statins. Other fibric acids and niacin are used, with caution, in combination with statins.

Cholestyramine (Questran) as well as colestipol (Colestid) bind statins in the intestine and reduce their absorption into the body. To prevent this binding within the intestine, statins should be taken one hour before or four hours after cholestyramine or colestipol.

Stains increase the effect of warfarin(Coumadin). Patients taking statins and warfarin should their blood clotting ability monitored carefully.

Fibric acid derivatives (fibrates) are a class of medication that lowers bloodtriglyceride levels. Fibrates lower blood triglyceride levels by reducing theliver's production of VLDL (the triglyceride-carrying particle that circulates in the blood) and by speeding up the removal of triglycerides from the blood.

Fibrates also are modestly effective in increasing blood HDL cholesterol levels; however, fibrates are not effective in lowering LDL cholesterol.

The side effects of fibrates include nausea, stomach upset, and sometimes diarrhea. Fibrates can irritate (inflame) the liver. The liver irritation usually is mild and reversible, but it occasionally can be severe enough to require stopping the drug.

Fibrates can cause gallstones when used for several years.

Fibrates can increase the effectiveness of blood thinners, such as warfarin (Coumadin), when both medications are used together. Thus, the dose of warfarin should be adjusted to avoid over-thinning of the blood which can lead to excessive bleeding.

Fibrates can cause muscle damage particularly when taken together with statin medications.

Gemfibrozil interferes with the breakdown of certainstatins (for example, simvastatin [Zocor] or lovastatin [Mevacor, Altoprev]), resulting in higher statin blood levels, and hence a higher likelihood of muscle toxicity from the statin

Fibrates can increase the effectiveness of blood thinners, such as warfarin(Coumadin), when both medications are used together. Thus, the dose of warfarin should be adjusted to avoid over-thinning of the blood which can lead to excessive bleeding.

Having enough niacin, or vitamin B3, in the body is important for general good health. As a treatment, higher amounts of niacin can improve cholesterol levels and lower cardiovascular risks.

As a cholesterol treatment, niacin has strong evidence. Several studies have shown that it can boost levels of good HDL cholesterol and lower triglycerides as well or better than some prescription drugs. Niacin also modestly lowers bad LDL cholesterol. It's often prescribed in combination with statins for cholesterol control, such as Crestor, Lescol, orLipitor.

Side effects. Niacin can cause flushing -- harmless but uncomfortable redness and warmth in the face and neck -- especially when you first begin taking it. Your health care provider will probably suggest increasing the dose slowly to reduce this problem. He or she might also offer a time-release prescription formulation to control flushing. Niacin can cause upset stomach and diarrhea. However, all of these side effects tend to fade over time.

Risks. Niacin does have risks. It can cause liver problems, stomach ulcers, changes to glucose levels, muscle damage, low blood pressure, heart rhythm changes, and other issues. People with any health condition including liver or kidney disease, diabetes,high blood pressure, or cardiovascular problems need to talk to a doctor before using niacin supplements. Do not treat high cholesterol on your own with over-the-counter niacin supplements.

Interactions. If you take any medicines or supplements regularly, talk to your doctor before you start using niacin supplements. They could interact with medicines like diabetes drugs, blood thinners, anticonvulsants, blood pressure medicines, thyroid hormones, and antibiotics as well as supplements like ginkgo biloba and some antioxidants.

Alcohol might increase the risk of liver problems. Though niacin is often used along with statins for high cholesterol, this combination may increase the risk for side effects. Get advice from your health care provider.

Labels have been revised to remove the need for routine periodic monitoring of liver enzymes in patients taking statins.

The labels now recommend that liver enzyme tests should be performed before starting statin therapy and as clinically indicated thereafter.

FDA has concluded that serious liver injury with statins is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.

The NLA or NCEP ATP-III guidelines do not provide specific recommendations for liver function monitoring with fibrate therapy.

 However, baseline measures, periodic follow-up monitoring, and reduction or discontinuation of therapy with transaminase levels ≥3 times the ULN is prudent.

Additionally, clinicians should be cognizant of factors that may increase risk of hepatotoxicity such as drug interactions or pre-existing liver disease.

Check lipids (fasting specimens required to quantify LDL fraction and triglycerides (TGs) accurately) and LFTs prior to starting treatment.

Take statins at night when they have a slightly greater effect.

Check U&Es prior to treatment, particularly if using in combination with a statin, as renal insufficiency increases the risk of myotoxicity. Adjust the dose if there is evidence of renal insufficiency. Routine ongoing monitoring of creatinine levels, etc is not required.

Discontinue the fibrate if serum aminotransferases are three or more times the upper limit of normal.

Check CK level only if myopathy or rhabdomyolysis is suspected: stop treatment if the CK level is five times the upper limit of normal or more.

The FDA recommends dose adjustment or cessation when these liver enzymes reach three times the upper limit of normal levels. Because of their once-a-day dosing, minimal side effects, and efficacy, the statins are considered a first-line drug therapy for dyslipidemias.

The fibrates work preferentially on the liver to reduce triglyceride synthesis and very low-density lipoprotein (VLDL) production. Fibrates also stimulate the uptake and metabolism of VLDL from the plasma, which can lead to increased LDL levels in patients who have very high baseline triglyceride levels.

They can reduce triglyceride levels markedly, and often produce a modest increase in HDL-C. However, they usually are dosed multiple times per day and may produce side effects, such as gallstones and gastrointestinal (GI) disturbances, including nausea and rash. However, for patients who predominantly have elevated triglycerides (type IV and V hyperlipidemias), they are considered first-line agents. Fibric acid derivatives should not be prescribed if a patient is receiving a statin.

 early symptoms of myopathy include muscle weakness, muscle pain or tenderness, muscle pain during exercise, and muscle fatigue. In some cases, patients with myopathy fall often, have trouble walking, or experience difficulty getting out of a chair.

Types of muscle proteins include the following: Creatine kinase (CK) Lactic dehydrogenase (LDH) Pyruvate kinase (PK)

As the disease progresses and muscle tissue wastes away, there is less and less protein to circulate and the amount in the blood drops to a normal level. The CK level is especially important in diagnosing Duchenne MD and the metabolic myopathies.

Patient Case #3: AL is a 57-year-old African American man with chronically elevated liver transaminases. He also has a history of type 2 DM and stroke.

His physician calls your pharmacy asking if you have any idea if he can use a statin medication in this patient. Currently he is taking colestipol for hyperlipidemia, but has discontinued this medication due to severe constipation. Patient denies any other complaints, including nausea, vomiting, abdominal pain or jaundice.

AL’s labs are as follows: LDL 168 mg/dL, TC 276 mg/dL, TG 332 mg/dL, and HDL 42 mg/dL. Patient’s AST and ALT have been consistently elevated between 1.1-1.4 times the upper

limit of normal (ULN) for years.

His total and direct bilirubin, INR, platelets, and albumin are all normal. Ultrasound of liver shows probable non-alcoholic fatty liver disease (NAFLD).

Elevations in liver aminotransferases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been demonstrated with all statins at all doses.

if elevations in AST and ALT are seen prior to statininitiation, the etiology should be determined and

referral to a hepatologist or gastroenterologist may be necessary.

If AST and ALT become elevated at any time during statin therapy, it remains prudent to determine the etiology of the abnormal tests to avoid discontinuation of statin therapy in high risk individuals.

if the AST and ALT are elevated between one to three times the ULN, then there is no need to change the patient’s lipid-lowering regimen.

The panel does believe decompensated cirrhosis and acute liver impairment are contraindications to statin therapy. Decompensated cirrhosis is cirrhosis associated with impaired liver function.

Patients would not only have elevated liver aminotransferases, but also have elevated indirect bilirubin, decreased albumin, decreased platelets, increased INR, and possibly bleeding varices

SOAP THIS CASE

Determine LDL goal

If the aminotransferases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are elevated you should stop Statins ( T / F )