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IATROGENIC ASPECTS OF LIPID-­LOWERING AGENTS Statins Statins (hydroxyl-­methyl-­glutaryl-­coenzyme A reductase [HMG-­CoA] inhibitors), discovered in the late 1970s, are one of the most prescribed classes of medi­ cation worldwide (1–5). The landmark Scandinavian Simvastatin Survival Study in the 1990s first established the long-­ term survival benefits of statins; since then, statins have been considered impor­ tant components of primary and secondary prevention of cardiovascular disease (CVD). According to a meta-­ analysis of more than 170,000 participants, statins-­ induced reduction of low-­ density lipoprotein (LDL) cholesterol by 40 mg/dl corresponds to a 10% reduction in all-­ cause mortality and a 20% reduction in coronary artery disease death, and the risks for coronary disease events and stroke ­ were attenuated by 23% and 17%, respectively (5). The clinical benefit results from the level of LDL lowering rather than from the statin used (3–11). The mechanism of action is based on the reduction of synthesis of cholesterol in the liver by inhibiting HMG-­ CoA reductase (1,8–11).The decrease in intracellular cholesterol levels ­ causes overexpression of LDL receptors on the hepatocyte cell surface, resulting in increased extraction of LDL cholesterol from the bloodstream and other apoB-­ containing lipoproteins, including triglyceride-­ rich particles. Aside from this main pathway of action, statins exert non-­ lipid-­ related pleiotropic properties (1,8). Side Effects of Statins­ There is ­ great heterogeneity in the absorption, bioavailability, plasma protein binding , excretion, and solubility of statins (1,7,9,10). ­ These characteristics, along with interindividual variation in response to statin therapy, determine not only the efficacy but also the safety of the lipid-­ lowering drugs (1,7). The lipophilicity and hydrophilicity CHAPTER 14 Iatrogenic Aspects of Lipid-­Lowering, Antiplatelet, and Anticoagulant Agents Konstantinos Tsioufis, Dimitris Konstantinidis, Nikolaos Vogiatzakis, Kyriakos Dimitriadis, and Dimitris Tousoulis 164 / Iatrogenic Aspects of Lipid-Lowering, Antiplatelet, and Anticoagulant Agents zation and mitochondrial function. Data suggest that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, each of which may contribute to the onset of muscle symptoms (8,9). Myalgia (without CPK elevation) is observed in 5% to 10% of patients receiving statins in clinical practice, but options other than stopping therapy are available. Dose reduction, statin change (discontinuation of potent statins such as atorvastatin and rosuvastatin), intermittent dosing , and drug combination are proposed methods to improve symptoms (8). When CPK elevations of 10 times ULN are pres­ ent, the term myopathy is used; its incidence is less than one per 10,000 per year with a standard statin dosage. When CPK is 4 times ULN, the statin should be stopped and its need reassessed based on the patient’s CVD risk. If continuation of therapy is mandatory, then a close follow-up of CPK levels is needed and therapy should be stopped when CPK is greater than 10 times ULN (1,8). Rhabdomyolysis is a severe form of muscle damage associated with very high CK levels, myoglobinemia and/or myoglobinuria, and high risk of renal failure and death. The incidence of rhabdomyolysis is one in 100,000 per year. ­ These patients, and ­ those with very high CPK levels (e.g., 40 times ULN), should be referred for evaluation of renal damage (urinalysis, serum creatinine levels). Intravenous hydration and urine alkalinization are recommended for the treatment of rhabdomyolysis depending on severity and the presence of kidney injury. If indicated, nonstatin LDL-­ C lowering agents should be used (1,8). Hepatic Elevations in liver enzymes are observed in 0.5% to 2% of patients on statin therapy. This occurs during the first months of statin administration and is dose dependent (1,7–10). ­ Because mea­ sur­ ing alanine aminotransferase and aspartate aminotransaminase in blood samples is the mainstay monitoring tool for liver toxicity in all statin ­ trials, data exist. A meaningful elevation of liver enzymes is considered a rise of three times the ULN on two separate occasions (with a time frame of several days to weeks). The mechanism of liver dysfunction could be due to induction of caspase activity, reduction of coenzyme Q10, or ­ free radical generation (1,7). of statins play a significant role in their adverse effects profile. Based on pathophysiology, muscle-­ related prob­ lems may be more prominent with lipophilic statins (e.g., atorvastatin, lovastatin, simvastatin) than with hydrophilic ones (e.g., pravastatin) (8,10). In general, statins are well tolerated and serious adverse events are rare. However, ­ there is a discrepancy between randomized controlled­ trials and observational studies related to the spectrum of...


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