Statins reduction

Pravastatin Pravochol HMG-CoA reductase inhibitor (statin) Reduction of LDL cholesterol levels by inhibiting cholesterol biosynthesis HOOC HO COO j H 1, OH... 

For ISIS 301012, a second-generation antisense inhibitor of apoB-100 in November 2006. Isis announced results from two Phase 2 clinical trials of ISIS 301012. In the first study repotted, patients with high cholesterol on stable doses of statins were treated with ISIS 301012 for 5 weeks. Patients who received 300 mg/week of ISIS 301012 in this study achieved a 51% reduction in LDL-cholesterol (LDL), a 42% reduction in total cholesterol (TC), and a 4l% reduction in triglycerides (TG) beyond the levels achieved with statins alone. 

Rate-limiting enzyme in cholesterol biosynthesis inhibition by statins results in reduction of plasma LDL-cholesterol levels. 

Several studies have investigated whether statins possess pharmacologic properties in addition to their LDL cholesterollowering effect that may confer additional benefits in IHD.24 These studies were prompted by evidence that patients with normal LDL cholesterol derived benefit from statins. Statins have been shown to modulate the following characteristics thought to stabilize atherosclerotic plaques and contribute to the cardiovascular risk reduction seen with these drugs ... 

Hyperlipidemia has not clearly been established as a risk factor for stroke, although it is a modifiable risk factor for coronary heart disease. Recent studies show that statin use may reduce the incidence of a first stroke in high-risk patients (e.g., hypertension, coronary heart disease, or diabetes) including patients with normal lipid levels. A recent meta-analysis showed a 25% risk reduction for fatal and non-fatal strokes with statin use.4 Patients with a history of MI, elevated lipid levels, diabetes, and... 

Combination drug therapy is an effective means to achieve greater reductions in LDL cholesterol (statin + ezetimibe or bile acid resin, bile acid resin + ezetimibe, or three-drug combinations) as well as raising HDL cholesterol and lowering serum triglycerides (statin + niacin or fibrate). 

Ezetimibe reduces LDL cholesterol by an average of 18% (Table 9-8). However, larger reductions can be seen in some individuals, presumably due to higher absorption of cholesterol. These individuals appear to have a blunted response to statin therapy. Ezetimibe lowers triglycerides by 7% to 9% and modestly increases HDL cholesterol. 

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%... 

A statin combined with a resin results in similar reductions in LDL cholesterol as those seen with ezetimibe. However, the magnitude of triglyceride reduction is less with a resin compared to ezetimibe, and this should be considered in patients with higher baseline triglyceride levels. In addition, gastrointestinal adverse events and potential drug interactions limit the utility of this combination. 

Some patients, in particular those with genetic forms of hypercholesterolemia (Table 9-2), will require three or more drugs to manage their disorder. Regimens using a statin, resin, and niacin were found to reduce LDL cholesterol up to 75%.42 These early studies were conducted with lovastatin, so larger reductions would be expected with the more potent statins available today. 

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. 

It would be very interesting to go back into the other cohorts, in which no difference in cholesterol reduction between the genotypes has been seen and to examine, whether the statin treatment also abolished excess mortality of apo E4 carriers. 

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. 

Ezetimibe interferes with the absorption of cholesterol from the brush border of the intestine, a novel mechanism that makes it a good choice for adjunctive therapy. It is approved as both monotherapy and for use with a statin. The dose is 10 mg once daily, given with or without food. When used alone, it results in an approximate 18% reduction in LDL cholesterol. When added to a statin, ezetimibe lowers LDL by about an additional 12% to 20%. A combination product (Vytorin) containing ezetimibe 10 mg and simvastatin 10, 20, 40, or 80 mg is available. Ezetimibe is well tolerated approximately 4% of patients experience GI upset. Because cardiovascular outcomes with ezetimibe have not been evaluated, it should be reserved for patients unable to tolerate statin therapy or those who do not achieve satisfactory lipid lowering with a statin alone. 

In general, a statin plus a BAR or niacin plus a BAR provide the greatest reduction in total and LDL cholesterol. 

Niacin (11) is the most potent HDL-raising drug (20-30%) on the market, and also provides some reduction in TG and LDL-C levels. Clinical studies with niacin as monotherapy or in combination with statins have yielded marked reductions in... 

The statins have been demonstrated to markedly lower plasma LDL levels (and triglyceride levels to a lesser extent). In fact, statins were approved by the US FDA on the basis of a surrogate endpoint reduction in plasma cholesterol levels. Since we know that increased plasma cholesterol levels are correlated with increased risk of coronary artery disease, it seems logical that reducing plasma cholesterol levels would lead to reduced risk. That turns out to be true in this case. However, see the case of hormone replacement therapy (HRT) for women for a more complex example, discussed below. 

The important point for patients is not so much that plasma cholesterol decreases but that the clinical endpoints decrease nonfatal heart attacks, coronary artery disease deaths, surgery for coronary artery disease, and total mortality. Subsequent to the approval of statins based on reduction of plasma cholesterol levels, several large, controlled clinical trials have been carried out to establish the effects of statin use on these clinical endpoints. ... 

Because the above trials showed a >50% relative reduction in total mortality with ICD therapy, MADIT II used broader entry criteria for primary prevention of SCD, removing the criteria for NSVT and EPS 1,232 patients with a history of MI > 30 days prior and an EF < 30% were randomized to conventional therapy or ICD implantation [10]. Conventional therapy was comparable in both arms and included a high rate of use of beta blockers, angiotensin-converting enzyme inhibitors, and statins (over two thirds for all medications in both arms). The trial was stopped early at 20 months because the relative reduction in total mortality... 

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