Cholesterol outcome studies

Outcome studies employing the statins have conclusively shown that reduction of LDL translates into reduced clinical cardiovascular events. However, in patients with normal LDL or after LDL levels have been normalized, TG and HDL levels assume an important role in the progression of atherosclerosis. The importance of HDL-cholesterol as an inverse... 

Cardiovascular As was reported in SEDA-32 (p. 817), ILLUMINATE, an outcome study that recruited around 15 000 statin-eligible patients with coronary heart disease or type 2 diabetes mellitus was terminated after a median follow-up of only 550 days, because of a small but significant increase in major cardiovascular events in those taking torcetrapib - - atorvastatin compared with those taking atorvastatin alone (49 versus 35 cardiovascular deaths) [69. This occurred despite a 72% increase in HDL cholesterol and a 25% reduction in LDL cholesterol compared with the statin alone. This was almost certainly correctly attributed to activation of the renin-angiotensin-aldosterone system, resulting in increments in blood pressure and aldosterone and reduced potassium. 

Oxidization of LDL-cholesterol is believed to play a significant role in the atherosclerotic process. The antioxidant vitamins, vitamin E and vitamin C, protect LDL cholesterol from oxidation. Evidence from observational and animal studies suggested that increased intake of antioxidant vitamins might inhibit the formation of atherosclerotic lesions and decrease the risk for cardiovascular events.40 However, several large, randomized, prospective studies found no beneficial effect of vitamin E or other antioxidants on cardiovascular outcomes in patients with IHD or IHD risk factors.41,42 Based on this evidence, current guidelines do not recommend supplementation with vitamin E or other antioxidants for the sole purpose of preventing cardiovascular events. 

Consequently, a more objective way to measure the habitual intake of milk fat would be the fatty acid composition of adipose tissue. However, this is not routinely performed in larger cohort studies, due to cost and that the procedure is invasive and less tolerated by study participants. Analysis of plasma fatty acid composition is thus a more feasible option for examination to determine dairy intake in the study population. While some groups have separated plasma into its constituent phospholipids and cholesterol esters to analyze serum 15 0 and 17 0 as markers of dairy intake (Smedman et al., 1999), Baylin et al. (2005) found that plasma that was not separated into its constituent cholesteryl ester, phospholipids, and triacylglycerols was still able to reflect habitual dairy intakes comparably to adipose tissue. Thus, whole plasma is an acceptable alternative to fractionated plasma in the absence of adipose tissue for analysis to reflect habitual dairy intakes and may be a cost effective option for consideration when conducting future intervention studies to assess the affect of dairy products on health outcomes. 

Atherosclerosis including acute coronary syndromes is an inflammatory process (37). Among biomarkers of inflammation, most attention and data has focused on C-reactive protein (CRP), which have been reported to be independently related to risk of future CHD events (38), Moreover, in the PROVE-IT TIMI 22 study, CRP levels at 30 days after treat-ment were not only independent of LDL cholesterol levels at that time but outcomes were improved in those who achieved not only an LDL cholesterol level of < 70 mg/dL (l.8mmol/L) but also CRP levels less than 2mg/L (39), However, uncertainties still remain and at this time it is considered premature to include CRP levels as a specific target,... 

The purpose of altering plasma lipoprotein levels is to reduce the risk of coronary events. The results of outcome trials are available for lovastatin (Downs et al, 1998), simvastatin (Scandinavian Simvastatin Survival Study Group 1994), and pravastatin (Shepherd et al, 1995 Sacks et al, 1996 The Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group, 1998). Three of these trials, 4S, Cholesterol and Recurrent Events (CARE), and LIPID, studied patients with CHD, whereas the West of Scotland Coronary Revention Study Group and the Air Force Coronary Atherosclesosis Prevention Study (AFCAPS) evaluated the benefits of therapy in patients without known CHD. The main results of these trials are summarized in Tables la and lb. 

Early investigations into a link between dietary tram fatty acid (TFA) intake and plasma cholesterol level in clinical trials, and CHD in epidemiology studies provided conflicting results. This outcome resulted from small numbers of participants in the trials combined with poor experimental... 

In addition to the effect of increased VLCFA on membrane and possibly cellular function, the rapid cerebral form of X-ALD is characterized by an inflammatory response that is believed to contribute to the demyelination that characterizes this phenotype and which is similar to that seen in multiple sclerosis. These cerebral lesions are characterized by breakdown in myelin with sparing of the axons accompanied by the accumulation of cholesterol ester in the neurons. A perivascular inflammatory response with infiltration of T cells, B cells, and macrophages also is present. Therefore, it is believed that the rapid cerebral disease has an im-munologically-mediated component. It has been suggested that the inflammatory response occurs in response to the elevated levels of VLCFA in lipids, which elicits an inflammatory cascade that may be mediated in part by cytokines. Once this cascade begins, it may be more difficult to intervene in the disease process, and in general therapeutic interventions studied to date have been most effective when initiated early. Therefore, prevention of the initiation of the immune response is important for improving outcome. 

More controversial is the extent to which primary prevention (treatment of clinically unaffected patients with moderate elevation of cholesterol levels) should include drugs, and whether secondary prevention should ever start with drugs rather than diet. Dietary treatment can lower cholesterol levels in committed subjects, and is obviously less costly than drug treatment. Unforhmately numerous studies have shown that over any substantial period of time (e.g. one year) diet has no clinically significant influence on plasma cholesterol and the wait for diet to have an effect often results in patients being lost from hospital follow-up after their initial myocardial infarction. Evidence comes from the WOSCOPS stud) in which pravastatin 40 mg/day and placebo were compared in 6590 men age 50-70 with LDL cholesterol 4-6 mmol/1 pravastatin reduced coronary heart disease (fatal and nonfatal events) by 31%. The authors estimated that treatment of 1000 such subjects each year would prevent 20 myocardial infarctions. Concerns that primary prevention could have a net adverse outcome (that cholesterol reduction increased the risk of cancer or violent deaths) have been laid to rest by a number of outcome trials. 

In another letter to the editor (12) it was mentioned that the suspicion of partiality about the Committee on Toxicity becomes more plausible when one considers the issue of homocysteine. This intermediate metabolite may well turn out to be of greater importance as a risk factor for cardiovascular disease than cholesterol and blood pressure. Raised homocysteine concentrations appear to be accessible to treatment with pyridoxine (100 mg/day) together with vitamin B12 and foUc acid (13). Furthermore, the statement that there is no good evidence for the efficacy of pyridoxine in any disease, apart from depression, was criticized, because this ignores important studies in autism, pregnancy outcome, asthma, and sickle-cell anemia (12). 

The Health Service reforms in the United Kingdom in 1991 avoided this trap and used instead the cost-utility concept. Cost-effectiveness takes into account only the cost of a single standardized outcome cost-utility looks at the costs of a range of different outcomes, such as extra years of survival and improved quality of life. A Dutch study of two cholesterol-lowering drugs, for example, showed that cholestyramine cost 131,000 Dutch Guilders per year of life saved compared with simvastatin which cost 31,500 Dutch Guilders. ... 

HDL cholesterol has also been the target of pharmacologic agents, with increases associated with improved cardiovascular outcomes. In the VA-HIT study by... 

---