Cholesterol trials

ARBITER, Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol trial. HALTS, HDL and LDL Treatment Strategies MI, myocardial infarction. 

Saponins. Although the hypocholesterolemic activity of saponins has been known since the 1950s, thek low potency and difficult purification sparked Htde interest in natural saponins as hypolipidemic agents. Synthetic steroids (292, 293) that are structurally related to saponins have been shown to lower plasma cholesterol in a variety of different species (252). Steroid (292) is designated CP-88,818 [99759-19-0]. The hypocholesterolemic agent CP-148,623 [150332-35-7] (293) is not absorbed into the systemic ckculation and does not inhibit enzymes involved in cholesterol synthesis, release, or uptake. Rather, (293) specifically inhibits cholesterol absorption into the intestinal mucosa (253). As of late 1996, CP-148,623 is in clinical trials as an agent that lowers blood concentrations of cholesterol (254). 

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

Derivatives of lovastatin have been found to be even more potent in cholesterol-lowering trials. Synvinolin lowers serum cholesterol levels at much lower doses than lovastatin. 

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). 

Cholesterol Treatment Trialists (CTT) Collaborators (2005) Efficacy and safety of cholesterol-lowering treatment prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 366 1267-1278... 

Grundy SM, Cleeman JT, Merz CN et al (2004) Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110 227-239... 

Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to improve vascular outcomes due to their cholesterol-lowering effects as well as multiple pleiotropic effects. In high-risk populations, statin therapy is known to reduce the risk of vascular events such as myocardial infarction and stroke. A meta-analysis of 10 trials involving 79,494 subjects showed that statin therapy reduced the incidence of stroke by 18%, major coronary events by 27%, and all-cause mortality by 15%. The SPARCL trial recently showed that high-dose HMG-CoA reductase inhibitors prevent recurrent stroke and transient ischemic attacks. ... 

Recent findings from the ATBC stndy even showed that P-carotene snpple-mentation increased the post-trial risk of a hrst-ever non-fatal MI. Two secondary prevention trials, the Heart Protection Stndy and the ATBC presented similar resnlts. The former showed no association between P-carotene and fatal or non-fatal vascular events and the latter reported signihcantly increased risks of fatal coronary events in the P-carotene-snpplemented gronp. Resnlts of clinical trials focused on the effects of carotenoids on CVD biomarkers are controversial. Although carotenoid supplementation increased sernm levels,only lycopene was shown to be inversely associated with lipid, protein, DNA and LDL oxidation, and plasma cholesterol levels. - - ... 

A fibrate derivative or niacin should be considered in select patients with a low high-density lipoprotein (HDL) cholesterol less than 40 mg/dL (1.04 mmol/L) and/or a high triglyceride level greater than 200 mg/dL (2.26 mmol/L). In a large randomized trial in men with established CAD and low levels of HDL cholesterol, the use of gemfibrozil (600 mg twice daily) significantly decreased the risk of non-fatal myocardial infarction or death from coronary causes.78... 

The benefits of lowering LDL cholesterol to as low as 70 mg/dL (1.81 mmol/L) have been demonstrated in clinical trials however, the lowest level at which to treat LDL cholesterol has not yet been determined. 

Therapeutic lifestyle changes should be the first approach tried in all patients (Table 9—7).3 An adequate trial of TLC should be employed in all patients, but pharmacotherapy should be instituted concurrently in higher-risk patients. This includes dietary restrictions of cholesterol and saturated fats as well as regular exercise and weight reduction. In addition, therapeutic options to enhance LDL cholesterol lowering such as consumption of plant stanols/sterols (which competitively inhibit incorporation of cholesterol into micelles) and dietary fiber should be encouraged. These therapeutic options collectively may reduce LDL cholesterol by 20% to 25%. 

Patients unable or unlikely to achieve their LDL cholesterol goals following a reasonable trial of TLC (typically 12 weeks for patients without CHD and sooner for those at high risk or... 

Therapeutic lifestyle changes should be continued and intensified (consider adding plant sterols/stanols and increase fiber) after 6 weeks if not below LDL cholesterol target. For those patients above their LDL cholesterol target after adequate trial of TLC (12 to 18 weeks), pharmacotherapy should be strongly considered. 

LT4 is indicated for patients with overt hypothyroidism.22 However, the need for treatment is controversial in patients with mild or subclinical disease (TSH less than 10 milli-units/L). There are no large clinical trials that show an outcome benefit with treating these patients, and the therapeutic decision must be individualized.1,23 Many patients with subclinical hypothyroidism do, in fact, have subtle symptoms that improve with LT4 replacement. If the patient s serum cholesterol is elevated,24 or if serum anti-TPOAbs are present, many clinicians recommend LT4 therapy. 

In addition to effects on bone, raloxifene may have effects in breast tissue and on the cardiovascular system. A secondary end point of the MORE trial evaluated the effects of raloxifene on the primary prevention of breast cancer and found a significant reduction in all types of breast cancer.33 Raloxifene decreases total and low-density lipoprotein (LDL) cholesterol,34 and studies are evaluating its effect on reducing the risk of cardiovascular disease.35... 

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