Statins combination therapy

Angiographic regression of coronary lesions with niacin-statin combination therapy (P<0.001 vs. placebo) clinical events reduced by 70% (P=0.03)... 

Okada K, Fukui K, Himeno H, Endo T, Shimizu M, Kobayashi S, Shigemasa T, Morita Y, Wada A, Shimizu T, Mochida Y, Sawada R, Ishigami T, Uchino K, Iwahashi N, Kimura K, Umemura S. Long-term effect of ezetimibe-statin combination therapy on low-density lipoprotein cholesterol lowering in patents with coronary artery disease focus on cholesterol absorption and synthesis. J. Am. Coll. Cardiol. 2011 57(14 Suppl S) E524. 

Resins are moderately effective in lowering LDL cholesterol but do not lower triglycerides (Table 9-8). Moreover, in patients with elevated triglycerides, the use of a resin may worsen the condition. This may be due to a compensatory increase in HMG-CoA reductase activity and results in an increase in assembly and secretion of VLDL. The increase in HMG-CoA reductase activity can be blocked with a statin, resulting in enhanced reductions in serum lipids (see section on combination therapy). Resins reduce LDL cholesterol from 15% to 30%, with a modest increase in HDL cholesterol (3% to 5%) (Table 9-8). Resins are most often used as adjuncts to statins in patients who require additional lowering of LDL cholesterol. Since these drugs are not absorbed, adverse effects are limited to the gastrointestinal tract (Table 9-9). About 20%... 

Fibrates are the most effective triglyceride-lowering agents and also raise HDL cholesterol levels. Combination therapy with a fibrate, particularly gemfibrozil, and a statin has been found to increase the risk for myopathy. Of the 31 rhabdomyolysis deaths reported with cerivastatin use, 12 involved concomitant gemfibrozil.25 Therefore, more frequent monitoring, thorough patient education, and consideration of factors that increase the risk as reviewed previously should be considered. 

Compared with monotherapy, combination therapy is relatively unstudied in terms of the effects on CHD event reduction and may reduce patient compliance through increased side effects and increased costs. When used appropriately and with proper precautions, however, they are effective in normalizing lipid abnormalities, particularly in patients who cannot tolerate adequate doses of statin therapy for more severe forms of dyslipidemia. 

Combination therapy with a statin and BAR is rational because numbers of LDL-Rs are increased, leadingto greater degradation of LDL cholesterol intracellular synthesis of cholesterol is inhibited and enterohepatic recycling of bile acids is interrupted. 

Combination therapy with a statin and ezetimibe is also rational because ezetimibe inhibits cholesterol absorption across the gut border and adds 12% to 20% further reduction when combined with a statin or other drugs. 

Fibrates are being combined with statins to expand their potential in the dyslipidemia market. A recent clinical study examined the effects of rosuvastatin (10) and fenofibrate as mono and combination therapy in hyperlipidemic diabetic patients [43]. In late 2006, large scale Phase III clinical trials of rosuvastatin in combination with a next-generation fibrate, ABT 335, were initiated for evaluation of safety and efficacy in patients with mixed dyslipidemia. 

At this time in clinical practice, the role of fibrates is particularly in combination therapy with a statin. Monitoring of creatine phosphokinase levels is appropriate because of the very small, although increased risk of rhabdomyolysis. 

The rate of myopathy with a statin alone in the general population is 0.1-0.5% and 0.2-2.5% with combination therapy. Rhabdomyolysis is very rare at 0.02-0.04%. However, the latter carries a significant morbidity and mortality. In a review of Food and Drug Administration (FDA) reports published in 2002, there were 38 deaths in 631 patients (6.3%) [31]. Pravastatin and fluvastatin have been less frequently implicated in fatal cases of rhabdomyolysis [31]. It is postulated that the more hepatoselective hydrophilic statins, such as pravastatin, are less likely to penetrate muscle cells than are lipophilic statins, and therefore represent a lower risk for myopathy, particularly in the event of an interacting drug increasing their blood levels to within the toxic range [26, 32]. 

Shek A, Ferrill MJ. Statin-fibrate combination therapy. Ann Pharmacother 2001 35 908-17. 

Patients not responding to statin monotherapy may be treated with combination therapy for hypercholesterolemia but should be monitored closely because of an increased risk for adverse effects and drug interactions. 

Drugs such as ezetimibe which inhibit the absorption of cholesterol in the intestine are effective in lowering cholesterol levels. This drug is often given in combination with a statin and this combination therapy is very effective in lowering cholesterol levels. 

Combination therapy with niacin and a statin has also been shown to produce clinical and angiographic benefits. Brown et al. (56) evaluated the effects of simvastatin in combination with niacin on patients with documented coronary disease in the HATS trial and demonstrated a significant reduction in nonfatal MI or death from cardiovascular causes compared to placebo, albeit with a relatively small number of patients. In the treatment arm, HDL cholesterol increased by 26% over the three years of treatment and was also associated with a slight regression (0.4%) in coronary mean percent stenosis in the proximal arteries by invasive arteriography the placebo arm experienced a 3.9% increase in stenoses. 

Renal failure is a relative contraindication to the use of fibric acid agents, as is hepatic dysfunction. Combined statin-fibrate therapy should be avoided in patients with compromised renal function. Gemfibrozil should be used with caution and at a reduced dosage to treat the hyperlipidemia of renal failure. Fibrates should not be used by children or pregnant women. 

Since myopathy rarely occurs in the absence of combination therapy, routine CK monitoring is not recommended unless the statins are used with a predisposing drug. Such monitoring is not sufficient to protect patients, as myopathy can occur months to years after combined therapy is initiated. a rule, statins may be combined with one of these predisposing drugs with reduced risk of myopathy if the statin is administered at no more than 25% of its maximal dose (e.g., 10 mg for rosuvastatin and 20 mg for all other statins). 

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