Statins clinical trials

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. 

The effect of statins on plasma lipids and lipoproteins is rapidly seen and fully achieved after 4-6 weeks of treatment. The effect persists unchanged during continued use for several years, but after stopping the diug, LDL-cholesterol rapidly increases to pretreatment levels. Treatment with statins is therefore usually continued indefinitely and not as a short-term cure. Finally, it is generally advisable to use the statins that have documented their efficacy in clinical trials (evidence-based medicine). 

Abdominal symptoms including changes in bowel function, rash, and disturbances of sleep have been reported, but in general statins are remarkably free of side effects. Thus, in the large clinical trials comprising... 

Once absorbed, ezetimibe undergoes extensive glucuronida-tion in the intestinal wall to the active metabolite (ezetimibe glucuronide). Ezetimibe and the active metabolite are entero-hepatically recirculated back to the site of action, which limits systemic exposure and may explain the low incidence of adverse effects (Table 9-9). Ezetimibe alone or with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in LFTs. Currently, clinical trials designed to determine ezetimibe s effects on CHD morbidity and mortality have not been completed. The time until maximum effect on lipids for ezetemibe is generally 2 weeks. 

Interest in the role of HMG-CoA reductase inhibitors (statins) in the treatment of osteoporosis came from boneforming properties seen in animal studies. However, controlled clinical trials are needed. 

Other agents, including selenium, vitamin E, lycopene, green tea, nonsteriodal anti-inflammatory agents, isoflavones, and statins, are under investigsation for prostate cancer and show promise. Selenium is a naturally occurring trace element that is an essential nutrient in the human diet.8 However, none of these agents is currently recommended for routine use outside a clinical trial. 

As indicated in Table 1, statins, which block cholesterol biosynthesis by inhibition of hepatic HMGCoA reductase, have been used extensively to reduce LDL-C levels. At most therapeutic doses, statins marginally increase HDL levels by 5-10% [3,16]. The HDL elevation observed with statins has been highly variable and not easily extrapolated from the effects on LDL. A recent study (STELLAR) demonstrated increased HDL elevation with the use of rosuvastatin compared to simvastatin, pravastatin or atorvastatin (10% vs. 2-6%) [16,24], Although the mechanism of HDL elevation by statins is not clearly understood, it is proposed that statins enhance hepatic apoA-I synthesis [25] and decrease apoB-containing lipoproteins [26]. A number of clinical trials have demonstrated that statins reduce the risk of major coronary events. However, it is not clear if the statin-induced rise in HDL levels is an independent contributor to the reduced risk of coronary events. The observed small increase in HDL and adverse side effect profile related to liver function abnormalities and muscle toxicity limits the use of statins as monotherapy for HDL elevation [27],... 

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. 

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. ... 

The results of several large clinical trials using the statin drugs (discussed later) show that the tested drugs decreased the risk of both primary and secondary cardiovascular events. The incidence of myocardial infarction and death from cardiovascular disease was reduced in patients with hypercholesterolemia who never had a... 

Some studies have shown increased risks of violent death and depression in subjects with reduced serum cholesterol concentrations. Serum and membrane cholesterol concentrations, the microviscosity of erythrocyte membranes, and platelet serotonin uptake have been determined in 17 patients with hypercholesterolemia (21). There was a significant increase in serotonin transporter activity only during the first month of simvastatin therapy. This suggests that within this period some patients could be vulnerable to depression, violence, or suicide. This is an important paper, in that it explains why mood disorders are not regularly seen in clinical trials with statins, as has been summarized in a recent review (3). 

Ross SD, Allen IE, Connelly JE, et al. Clinical outcomes in statin treatment trials a meta-analysis. Arch Intern Med. 1999 159 1793-1802. 

Several randomized clinical trials of lipid lowering therapy with statins have been conducted in patients with acute... 

The earlier appearance of clinical benefit in statin lipidlowering trials compared to nonstatin lipid-lowering trials despite significant reductions in LDL cholesterol,... 

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