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Division of Endocrinology, Department of Internal Medicine, Saint Louis University, St. Louis, Missouri.
Address correspondence to Arshag D. Mooradian, MD, Division of Endocrinology, Department of Internal Medicine, Saint Louis University Hospital, 3635 Vista at Brand Blvd., FDT-14th Floor, St. Louis, MO 63110-0259. E-mail: mooradad{at}slu.edu
It is generally accepted that statin therapy reduces morbidity and mortality associated with cardiovascular disease (CVD). However, there are still two fundamental questions that remain incompletely answered. First, how low should low-density lipoprotein (LDL) cholesterol go to achieve maximal benefits, and second, what, if any, is the relative contribution of noncholesterol-lowering effects of statins (i.e., pleiotropic effects) to their cardioprotective properties. The post hoc analysis of the data from some secondary prevention trials, such as the CARE and the LIPID trials, suggest that the relationship between LDL cholesterol and CVD events is curvilinear with the benefits of statins phasing out at a LDL cholesterol level below approximately 125 mg/dl [Reviewed in (1)]. In contrast, the data in the 4S trial suggest a more linear relationship between the LDL cholesterol level and CVD events, while in the HPS, the simvastatin effect was independent of baseline LDL cholesterol levels and the cardiovascular events were reduced with statin therapy even in those persons with LDL cholesterol levels well within the currently recommended target for high-risk populations of less than 100 mg/dl (1). Finally, convincing evidence has been emerging to indicate that in very high risk groups, such as those experiencing acute coronary syndromes, the LDL cholesterol goal should be reduced from the current guidelines of less than 100 mg/dl to less than 70 mg/dl (2). The latter goal was recently supported by the results of the TNT trial (3). As for the majority of patients requiring primary or secondary prevention, the question of whether to lower LDL cholesterol below 70 or 80 mg/dl still remains unresolved, and will have to be reexamined in soon-to-be completed trials such as the SEARCH trial (4).
Although the data are limited, it appears that the beneficial effects of statin therapy, especially in high-risk groups, are independent of age (1). However, age per se, is a major risk factor for CVD, and the relative contribution of cholesterol to CVD in elderly people is lower compared to younger counterparts (5). This raises the question whether the pleiotropic effects of statins are sufficient to maintain their cardioprotective properties in elderly persons. It is noteworthy that many of the pleiotropic effects of statins are the result of inhibition of hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity (6). Thus, it is possible that the level of LDL cholesterol reduction also serves as an index, albeit incomplete, of the pleiotropic effects. The continued clinical efficacy of statins in elderly people may well be the result of cholesterol lowering and cholesterol independent effects. The relative contribution of the latter effects may be increased with advancing age. This speculation needs to be tested empirically.
Overall, it appears that both young and elderly subjects who are at very high risk of cardiovascular death, such as those experiencing acute coronary syndromes, should be started on potent statins, and the LDL cholesterol target should be lowered to less than 70 mg/dl. For the rest, the current NCEP III guidelines are adequate pending the release of the results from ongoing trials designed to determine future goals of therapy.
References
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| All GSA journals | The Gerontologist |
| Journals of Gerontology Series B: Psychological Sciences and Social Sciences | |
